Proteasomal Inhibition Attenuates Transcriptional Activity of Hypoxia-Inducible Factor 1 (HIF-1) via Specific Effect on the HIF-1α C-Terminal Activation Domain
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The ubiquitin-proteasome pathway (UPP) is involved in regulation of multiple cellular processes. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is a prototypic target of the UPP and, as such, is stabilized under conditions of proteasomal inhibition. Using carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) expression as paradigmatic markers of HIF-1 activity, we found that proteasomal inhibitors (PI) abrogated hypoxia-induced CAIX expression in all cell lines tested and VEGF expression in two out of three. Mapping of the inhibitory effect identified the C-terminal activation domain (CAD) of HIF-1 alpha as the primary target of PI. PI specifically inhibited the HIF-1 alpha CAD despite activating the HIF-1 alpha coactivator p300 and another p300 cysteine/histidine-rich domain 1-dependent transcription factor, STAT-2. Coimmunoprecipitation and glutathione S-transferase pull downs indicated that PI does not disrupt interactions between HIF-1 alpha and p300. Mutational analysis failed to confirm involvement of sites of known or putative posttranslational modifications in regulation of HIF-1 alpha CAD function by PI. Our data provide evidence for the counterintuitive hypothesis that inhibition of HIF-1 function could be responsible for at least some of the antitumor effects of proteasomal inhibition. Further studies of the mechanism of the PI-induced attenuation of HIF-1alpha will provide important, potentially novel insight into regulation of HIF-1 activity and possibly identify new targets for HIF-directed therapy.
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Bortezomib is associated with suppression of HIF-1 signaling despite expectation that proteasome inhibition would stabilize HIF-α subunits.
“bortezomib, a clinically approved proteasome inhibitor used in multiple myeloma, has been repeatedly associated with suppression of HIF-1 signaling, despite the expectation that proteasome inhibition would stabilize HIF-α subunits [[336], [337], [338]].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [336]
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Cites
Hershko, A., & Ciechanover, A. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.425 · Cited by 8,840 · see citing works
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · see citing works
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212 · see citing works
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180 · see citing works
Hypoxia — a key regulatory factor in tumour growth
Harris, A. L. (2002) · Nature Reviews Cancer · doi:10.1038/nrc704 · Cited by 5,177 · see citing works
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · cited 4× · see citing works
“Hydroxylated prolines enable specific recognition of HIF-1 by the von Hippel-Lindau protein (VHL) (23, 25), which, in a complex with elongin B, elongin C, and Cul2 (22), functions as an E3 ubiquitin ligase for HIF-1 (49).”
BackgroundInfluentialMdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506 · see citing works
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333 · see citing works
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · see citing works
A conserved family of prolyl-4-hydroxylases that modify HIF
Bruick, R. K., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1066373 · Cited by 2,549 · see citing works
NF-κB in cancer: from innocent bystander to major culprit
Karin, M., Cao, Y., Greten, F. R., & Li, Z. (2002) · Nature reviews. Cancer · doi:10.1038/nrc780 · Cited by 2,476 · see citing works
Huang, L. E., Gu, J., Schau, M., & Bunn, H. F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.7987 · Cited by 2,113 · see citing works
Regulation of Mammalian O <sub>2</sub> Homeostasis by Hypoxia-Inducible Factor 1
Semenza, G. L. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.551 · Cited by 1,914 · see citing works
Salceda, S., & Caro, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.36.22642 · Cited by 1,674 · see citing works
Ohh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T.-Y., Huang, L. E., Pavletich, N., Chau, V., & Kaelin, W. G. (2000) · Nature Cell Biology · doi:10.1038/35017054 · Cited by 1,577 · see citing works
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L. (2002) · Science · doi:10.1126/science.1068592 · Cited by 1,558 · see citing works
Lando, D., Peet, D. J., Gorman, J. J., Whelan, D. A., Whitelaw, M. L., & Bruick, R. K. (2002) · Genes & Development · doi:10.1101/gad.991402 · Cited by 1,550 · cited 1× · see citing works
“by on January 22, 2010 mcb.asm.org Downloaded from mal activity ( 38 ).”
BackgroundMahon, P. C., Hirota, K., & Semenza, G. L. (2001) · Genes & Development · doi:10.1101/gad.924501 · Cited by 1,385 · see citing works
Hypoxia-inducible expression of tumor-associated carbonic anhydrases.
Wykoff, C. C., Beasley, N. J. P., Watson, P. H., Turner, K., Pastorek, J., Sibtain, A., Wilson, G. D., Turley, H., Talks, K., Maxwell, P. H., et al. (2000) · PubMed · Cited by 1,258 · see citing works
The proteasome: a suitable antineoplastic target
Adams, J. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1361 · Cited by 1,200 · see citing works
Proteasome inhibitors: from research tools to drug candidates.
Kisselev, A., & Goldberg, A. (2001) · Chemistry and Biology · doi:10.1016/s1074-5521(01)00056-4 · Cited by 1,176 · see citing works
Gao, X., Wu, G., Gu, X., Fu, L., & Mei, C. (2013) · Kidney & Blood Pressure Research · doi:10.1159/000355743 · Cited by 1,036 · see citing works
NF-κB as a Therapeutic Target in Multiple Myeloma
Hideshima, T., Chauhan, D., Richardson, P. G. G., Mitsiades, C. S., Mitsiades, N., Hayashi, T., Munshi, N. C., Dang, L., Castro, A. C., Palombella, V. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200360200 · Cited by 894 · see citing works
CREB-binding Protein and p300 in Transcriptional Regulation
Vo, N., & Goodman, R. H. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.r000025200 · Cited by 868 · see citing works
An essential role for p300/CBP in the cellular response to hypoxia
Arany, Z., Huang, L. E., Eckner, R., Bhattacharya, S., Jiang, C., Goldberg, M. A., Bunn, H. F., & Livingston, D. M. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.23.12969 · Cited by 790 · see citing works
The development of proteasome inhibitors as anticancer drugs
Adams, J. (2004) · Cancer Cell · doi:10.1016/s1535-6108(04)00120-5 · Cited by 778 · see citing works
Regulation of the Hypoxia-inducible Transcription Factor 1α by the Ubiquitin-Proteasome Pathway
Kallio, P. J., Wilson, W. J., O’Brien, S. L., Makino, Y., & Poellinger, L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.10.6519 · Cited by 754 · see citing works
Expression of Hypoxia-Inducible Cell-Surface Transmembrane Carbonic Anhydrases in Human Cancer
Ivanov, S. V., Liao, S., Ivanova, A. V., Danilkovitch‐Miagkova, A., Tarasova, N. I., Weirich, G., Merrill, M. J., Proescholdt, M. A., Oldfield, E. H., Lee, J., et al. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64038-2 · Cited by 681 · see citing works
Self-citationHIF-1 as a target for drug development
Giaccia, A., Siim, B. G., & Johnson, R. S. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1199 · Cited by 631 · see citing works
Transactivation and Inhibitory Domains of Hypoxia-inducible Factor 1α
Jiang, B.-H., Zheng, J. Z., Leung, S. W., Roe, R., & Semenza, G. L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.31.19253 · Cited by 629 · see citing works
The proteasome: structure, function, and role in the cell
Adams, J. N. (2003) · Cancer Treatment Reviews · doi:10.1016/s0305-7372(03)00081-1 · Cited by 583 · see citing works
Lonard, D. M., Nawaz, Z., Smith, C. L., & O’Malley, B. W. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80259-2 · Cited by 559 · see citing works
Activation of Hypoxia-inducible Factor-1; Definition of Regulatory Domains within the α Subunit
Pugh, C. W., O'Rourke, J. F., Nagao, M., Gleadle, J., & Ratcliffe, P. J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.17.11205 · Cited by 526 · see citing works
Suppression of tumor growth through disruption of hypoxia-inducible transcription
Kung, A. L., Wang, S., Klco, J. M., Kaelin, W. G., & Livingston, D. M. (2000) · Nature Medicine · doi:10.1038/82146 · Cited by 501 · see citing works
Cooperation of Stat2 and p300/CBP in signalling induced by interferon-α
Bhattacharya, S., Eckner, R., Grossman, S., Oldread, E., Arany, Z., D'Andrea, A., & Livingston, D. M. (1996) · Nature · doi:10.1038/383344a0 · Cited by 493 · see citing works
Loncaster, J. A., Harris, A. L., Davidson, S. E., Logue, J. P., Hunter, R. D., Wycoff, C. C., Pastorek, J., Ratcliffe, P. J., Stratford, I. J., & West, C. (2001) · PubMed · Cited by 482 · see citing works
Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway
Kung, A. L., Zabludoff, S. D., France, D. S., Freedman, S. J., Tanner, E. A., Vieira, A., Cornell-Kennon, S., Lee, J., Wang, B., Wang, J., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.009 · Cited by 480 · see citing works
Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1α
Freedman, S. J., Sun, Z., Poy, F., Kung, A. L., Livingston, D. M., Wagner, G., & Eck, M. J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.082117899 · Cited by 457 · see citing works
LeBlanc, R., Catley, L. P., Hideshima, T., Lentzsch, S., Mitsiades, C. S., Mitsiades, N., Neuberg, D. S., Goloubeva, O. G., Pien, C. S., Adams, J., et al. (2002) · PubMed · Cited by 455 · see citing works
Structural basis for Hif-1α/CBP recognition in the cellular hypoxic response
Dames, S. A., Martinez‐Yamout, M. A., Guzman, R. N. D., Dyson, H. J., & Wright, P. E. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.082121399 · Cited by 404 · see citing works
Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1Preprint
Bhattacharya, S., Michels, C. L., Leung, M.-K., Arany, Z. P., Kung, A. L., & Livingston, D. M. (1999) · Genes & Development · doi:10.1101/gad.13.1.64 · Cited by 392 · see citing works
Sowter, H., Raval, R. R., Moore, J. W., Ratcliffe, P. J., & Harris, A. L. (2003) · PubMed · Cited by 374 · see citing works
MAPK Signaling Up-regulates the Activity of Hypoxia-inducible Factors by Its Effects on p300
Sang, N., Stiehl, D. P., Bohensky, J., Leshchinsky, I., Srinivas, V., & Caro, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209702200 · Cited by 370 · see citing works
Hypoxia-inducible Factor and Its Biomedical Relevance
Huang, E. L., & Bunn, H. F. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.r200030200 · Cited by 313 · see citing works
Mabjeesh, N. J., Post, D. E., Willard, M. T., Kaur, B., Meir, E. G. V., Simons, J. W., & Zhong, H. (2002) · PubMed · Cited by 299 · see citing works
p53 Inhibits Hypoxia-inducible Factor-stimulated Transcription
Blagosklonny, M. V., An, W. G., Romanova, L. Y., Trepel, J. B., Fojo, T., & Neckers, L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.20.11995 · Cited by 284 · see citing works
Roccaro, A. M., Hideshima, T., Raje, N. S., Kumar, S. K., Ishitsuka, K., Yasui, H., Shiraishi, N., Ribatti, D., Nico, B., Vacca, A., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-1195 · Cited by 283 · see citing works
Damert, A., Ikeda, E., & Risau, W. (1997) · Biochemical Journal · doi:10.1042/bj3270419 · Cited by 216 · see citing works
The von Hippel–Lindau tumor suppressor protein
Ivan, M., & Kaelin, W. G. (2001) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(00)00152-0 · Cited by 211 · see citing works
Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer.
Olive, P. L., Aquino‐Parsons, C., MacPhail, S. H., Liao, S. Y., Raleigh, J. A., Lerman, M. I., & Stanbridge, E. J. (2001) · PubMed · Cited by 208 · see citing works
Self-citationA putative stimulatory role for activator turnover in gene expression
Lipford, J., Smith, G. T., Chi, Y., & Deshaies, R. J. (2005) · Nature · doi:10.1038/nature04098 · Cited by 198 · see citing works
Mizukami, Y., Li, J., Zhang, X., Zimmer, M. A., Iliopoulos, O., & Chung, D. C. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-3017 · Cited by 165 · see citing works
Pal, S., Claffey, K. P., Cohen, H. T., & Mukhopadhyay, D. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.41.26277 · Cited by 162 · see citing works
Kaluz, Š., Kaluzová, M., Chrastina, A., Olive, P. L., Pastoreková, S., Pastorek, J., Lerman, M. I., & Stanbridge, E. J. (2002) · PubMed · Cited by 149 · see citing works
Self-citationMolecular Mechanism of Hypoxia-inducible Factor 1α-p300 Interaction
Gu, J., Milligan, J., & Huang, E. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009522200 · Cited by 130 · see citing works
Wang, D., Moriggl, R., Stravopodis, D. J., Carpino, N., Marine, J., Teglund, S., Feng, J., & Ihle, J. N. (2000) · The EMBO Journal · doi:10.1093/emboj/19.3.392 · Cited by 121 · see citing works
Rafajová, M., Zaťovičová, M., Kettmann, R., Pastorek, J., & Pastoreková, S. (2004) · International Journal of Oncology · doi:10.3892/ijo.24.4.995 · Cited by 119 · see citing works
Gradin, K., Takasaki, C., Fujii‐Kuriyama, Y., & Sogawa, K. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201307200 · Cited by 105 · see citing works
MacKay, H. J., Hedley, D. W., Major, P. P., Townsley, C. A., MacKenzie, M. J., Vincent, M. D., Degendorfer, P., Tsao, M., Nicklee, T., Birle, D. C., et al. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-0081 · Cited by 103 · see citing works
Kaluzová, M., Kaluz, Š., Lerman, M. I., & Stanbridge, E. J. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.13.5757-5766.2004 · Cited by 83 · see citing works
Self-citationKaluz, Š., Kaluzová, M., & Stanbridge, E. J. (2003) · PubMed · Cited by 78 · see citing works
Self-citationTranscriptional Regulation of the MN/CA 9 Gene Coding for the Tumor-associated Carbonic Anhydrase IX
Kaluz, Š., Kaluzová, M., Opavský, R., Pastoreková, S., Gibadulinová, A., Dequiedt, F., Kettmann, R., & Pastorek, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.46.32588 · Cited by 60 · see citing works
Kaluzová, M., Pastoreková, S., Švastová, E., Pastorek, J., Stanbridge, E. J., & Kaluz, Š. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3590669 · Cited by 44 · see citing works
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Flagged first, then by citations
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Sorted by citations
HIF-1α pathway: role, regulation and intervention for cancer therapy
Masoud, G. N., & Li, W. (2015) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2015.05.007 · Cited by 1,871 · see citing works
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
Semenza, G. L. (2010) · Oncogene · doi:10.1038/onc.2009.441 · Cited by 1,712 · see citing works
Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy
Semenza, G. L. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.01.005 · Cited by 1,514 · see citing works
Hypoxia signalling through mTOR and the unfolded protein response in cancer
Wouters, B. G., & Koritzinsky, M. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2501 · Cited by 894 · see citing works
Hypoxia and hypoxia-inducible factors: master regulators of metastasis
Lu, X., & Kang, Y. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1360 · Cited by 723 · see citing works
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
Wigerup, C., Påhlman, S., & Bexell, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.009 · Cited by 687 · see citing works
“…HRE Kong et al., 2005 Polyamides HRE Olenyuk et al., 2004 Transcriptional activity Chetomin p300 recruitment Kung et al., 2004 Bortezomib p300 recruitment Kaluz et al., 2006, Shin et al., 2008 Amphotericin B FIH-1 interaction and p300 recruitment Yeo et al., 2006 Triptolide Hsp70 Zhou et al.,…”
BackgroundRohwer, N., & Cramer, T. (2011) · Drug Resistance Updates · doi:10.1016/j.drup.2011.03.001 · Cited by 608 · see citing works
Tumor and its microenvironment: A synergistic interplay
Catalano, V., Turdo, A., Franco, S. D., Dieli, F., Todaro, M., & Stassi, G. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.08.007 · Cited by 436 · see citing works
Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases
Eltzschig, H. K., Bratton, D. L., & Colgan, S. P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4422 · Cited by 363 · see citing works
Evaluation of HIF-1 inhibitors as anticancer agents
Semenza, G. L. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.08.006 · Cited by 363 · see citing works
Mechanisms of proteasome inhibitor action and resistance in cancer
McConkey, D. J., & Zhu, K. (2008) · Drug Resistance Updates · doi:10.1016/j.drup.2008.08.002 · Cited by 309 · see citing works
Pharmacologic Targeting of Hypoxia-Inducible Factors
Semenza, G. L. (2019) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021637 · Cited by 288 · see citing works
Ubiquitin and Proteasomes in Transcription
Geng, F.-Q., Wenzel, S., & Tansey, W. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-052110-120012 · Cited by 302 · see citing works
Cellular Stress Response Pathway System as a Sentinel Ensemble in Toxicological Screening
Simmons, S. O., Fan, C., & Ramabhadran, R. (2009) · Toxicological Sciences · doi:10.1093/toxsci/kfp140 · Cited by 280 · see citing works
Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors
Xia, Y., Choi, H.-K., & Lee, K. (2012) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2012.01.033 · Cited by 278 · see citing works
Role of hypoxia-inducible factors in breast cancer metastasis
Gilkes, D. M., & Semenza, G. L. (2013) · Future Oncology · doi:10.2217/fon.13.92 · Cited by 274 · see citing works
Development of HIF‐1 inhibitors for cancer therapy
Onnis, B., Rapisarda, A., & Melillo, G. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00876.x · Cited by 268 · see citing works
Kaluz, Š., Kaluzová, M., Liao, S., Lerman, M. I., & Stanbridge, E. J. (2009) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2009.01.001 · Cited by 251 · see citing works
Self-citationPotts, B. C. M., Albitar, M. X., Anderson, K. C., Baritaki, S., Berkers, C. R., Bonavida, B., Chandra, J., Chauhan, D., Cusack, J. C., Fenical, W., et al. (2011) · Current Cancer Drug Targets · doi:10.2174/156800911794519716 · Cited by 247 · see citing works
Targeting hypoxia cell signaling for cancer therapy
Melillo, G. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9059-x · Cited by 230 · see citing works
Molecular mechanisms mediating metastasis of hypoxic breast cancer cells
Semenza, G. L. (2012) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2012.08.001 · Cited by 217 · see citing works
The hypoxic microenvironment: A determinant of cancer stem cell evolution
Carnero, A., & LLeonart, M. E. (2016) · BioEssays · doi:10.1002/bies.201670911 · Cited by 201 · see citing works
HIFs, angiogenesis, and cancer
Yang, Y., Sun, M., Wang, L., & Jiao, B. (2012) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24438 · Cited by 189 · see citing works
Metabolic adaptation of cancer and immune cells mediated by hypoxia-inducible factors
Samanta, D., & Semenza, G. L. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.07.002 · Cited by 190 · see citing works
Interfering with Tumor Hypoxia for Radiotherapy Optimization
Telarović, I., Wenger, R. H., & Pruschy, M. N. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02000-x · Cited by 196 · see citing works
Yang, L., Lin, C., Wang, L., Guo, H., & Wang, X. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2012.07.017 · Cited by 179 · see citing works
Kaluz, Š., Kaluzová, M., & Stanbridge, E. J. (2008) · Clinica Chimica Acta · doi:10.1016/j.cca.2008.05.002 · Cited by 171 · see citing works
Self-citationShin, D. H., Chun, Y., Lee, D. S., Huang, E. L., & Park, J. (2008) · Blood · doi:10.1182/blood-2007-11-120576 · Cited by 163 · see citing works
Li, S. H., Shin, D. H., Chun, Y.-S., Lee, M. K., Kim, M.-S., & Park, J.-W. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0074 · Cited by 160 · see citing works
Hypoxia Inducible Factor Pathway Inhibitors as Anticancer Therapeutics
Burroughs, S. K., Kaluz, S., Wang, D., Wang, K., Van Meir, E. G., & Wang, B. (2013) · Future Medicinal Chemistry · doi:10.4155/fmc.13.17 · Cited by 140 · see citing works
Hypoxia-Inducible Factor-1: A Critical Player in the Survival Strategy of Stressed Cells
Chen, S., & Sang, N. (2015) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25283 · Cited by 135 · see citing works
Befani, C. D., Vlachostergios, P. J., Hatzidaki, E., Patrikidou, A., Bonanou, S., Simos, G., Papandreou, C. N., & Liakos, P. (2012) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0805-8 · Cited by 135 · see citing works
The emerging role of hypoxia, HIF-1 and HIF-2 in multiple myeloma
Martin, S. K., Diamond, P., Gronthos, S., Peet, D. J., & Zannettino, A. C. W. (2011) · Leukemia · doi:10.1038/leu.2011.122 · Cited by 126 · see citing works
The potential role of HIF on tumour progression and dissemination
Unwith, S., Zhao, H., Hennah, L., & Ma, D. (2014) · International Journal of Cancer · doi:10.1002/ijc.28889 · Cited by 126 · see citing works
Qannita, R. A., Alalami, A., Harb, A. A., Aleidi, S. M., Taneera, J., Abu‐Gharbieh, E., El‐Huneidi, W., Saleh, M. A., Alzoubi, K. H., Semreen, M. H., et al. (2024) · Pharmaceuticals · doi:10.3390/ph17020195 · Cited by 122 · see citing works
Glioblastoma, Cancer Stem Cells and Hypoxia
Bar, E. E. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2010.00460.x · Cited by 117 · see citing works
Terzuoli, E., Puppo, M., Rapisarda, A., Uranchimeg, B., Cao, L., Burger, A. M., Ziche, M., & Melillo, G. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1075 · Cited by 111 · see citing works
Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy
Martínez‐Sáez, O., Borau, P. G., Alonso‐Gordoa, T., Molina‐Cerrillo, J., & Grande, E. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.01.013 · Cited by 109 · see citing works
Hypoxia and the Malignant Glioma Microenvironment: Regulation and Implications for Therapy
Oliver, L., Olivier, C., Marhuenda, F., Campone, M., & Vallette, F. M. (2009) · Current Molecular Pharmacology · doi:10.2174/1874467210902030263 · Cited by 102 · see citing works
Expression of transmembrane carbonic anhydrases, CAIX and CAXII, in human development
Liao, S., Lerman, M. I., & Stanbridge, E. J. (2009) · BMC Developmental Biology · doi:10.1186/1471-213x-9-22 · Cited by 92 · see citing works
Self-citationThe induction of HIF‐1 reduces astrocyte activation by amyloid beta peptide
Schubert, D. A., Soucek, T., & Blouw, B. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.06712.x · Cited by 89 · see citing works
Effects of Histone Deacetylase Inhibitors on HIF-1
Liang, D., Kong, X., & Sang, N. (2006) · Cell Cycle · doi:10.4161/cc.5.21.3409 · Cited by 85 · see citing works
Yoshii, Y., Furukawa, T., Waki, A., Okuyama, H., Inoue, M., Itoh, M., Zhang, M.-R., Wakizaka, H., Sogawa, C., Kiyono, Y., et al. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2015.02.008 · Cited by 66 · see citing works
Melatonin and the von Hippel–Lindau/HIF-1 oxygen sensing mechanism: A review
Vriend, J. P., & Reiter, R. J. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.02.004 · Cited by 64 · see citing works
Wang, L., Chen, G., Lu, X., Wang, S., Han, S., Li, Y., Ping, G., Jiang, X., Li, H., Yang, J., et al. (2015) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.10.036 · Cited by 64 · see citing works
HIF-1alpha and infectious diseases: a new frontier for the development of new therapies
dos Santos, S. A., & de Andrade, D. R. (2017) · Revista do Instituto de Medicina Tropical de São Paulo · doi:10.1590/s1678-9946201759092 · Cited by 62 · see citing works
Shafee, N., Kaluz, Š., Ru, N., & Stanbridge, E. J. (2009) · Cancer Letters · doi:10.1016/j.canlet.2009.03.004 · Cited by 60 · see citing works
Self-citationRegulation of Vascularization by Hypoxia‐Inducible Factor 1
Semenza, G. L. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05032.x · Cited by 59 · see citing works
Birle, D. C., & Hedley, D. W. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2722 · Cited by 58 · see citing works
Hypoxia-regulated gene network in drug resistance and cancer progression
Lin, S.-C., Liao, W.-L., Lee, J., & Tsai, S. (2014) · Experimental Biology and Medicine · doi:10.1177/1535370214532755 · Cited by 57 · see citing works
Control of HIF-1α Expression by eIF2α Phosphorylation–Mediated Translational Repression
Zhu, K., Chan, W., Heymach, J., Wilkinson, M., & McConkey, D. J. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4103 · Cited by 55 · see citing works
Targeting hypoxia in solid and haematological malignancies
Harris, B., Saleem, S., Cook, N., & Searle, E. J. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02522-y · Cited by 54 · see citing works
Hu, Y., Kirito, K., Yoshida, K., Mitsumori, T., Nakajima, K., Nozaki, Y., Hamanaka, S., Nagashima, T., Kunitama, M., Sakoe, K., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0150 · Cited by 52 · see citing works
Design and Synthesis of Novel Small-Molecule Inhibitors of the Hypoxia Inducible Factor Pathway
Mooring, S. R., Jin, H., Devi, N. S., Jabbar, A. A., Kaluz, Š., Liu, Y., Meir, E. G. V., & Wang, B. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm201018g · Cited by 50 · see citing works
Womeldorff, M. R., Gillespie, D. L., & Jensen, R. L. (2014) · Neurosurgical FOCUS · doi:10.3171/2014.9.focus14496 · Cited by 50 · see citing works
Acetazolamide potentiates the anti-tumor potential of HDACi, MS-275, in neuroblastoma
Mokhtari, R. B., Baluch, N., Tsui, M., Kumar, S., Homayouni, T. S., AITKEN, K. J., Das, B., Baruchel, S., & Yeger, H. (2017) · BMC Cancer · doi:10.1186/s12885-017-3126-7 · Cited by 45 · see citing works
Hypoxia-inducible factor 2α: a novel target in gliomas
Renfrow, J. J., Soike, M. H., Debinski, W., Ramkissoon, S. H., Mott, R. T., Frenkel, M. B., Sarkaria, J. N., Lesser, G. J., & Strowd, R. E. (2018) · Future Medicinal Chemistry · doi:10.4155/fmc-2018-0163 · Cited by 40 · see citing works
Park, T. H., Lee, S. H., Park, Y. J., Lee, Y., Rah, D. K., & Kim, S. Y. (2015) · Annals of Plastic Surgery · doi:10.1097/sap.0000000000000435 · Cited by 40 · see citing works
Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review
Kiran, D., & Basaraba, R. J. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.624607 · Cited by 39 · see citing works
Lactate stimulates CA IX expression in normoxic cancer cells
Pánisová, E., Kery, M., Sedlakova, O., Brisson, L., Debreova, M., Sboarina, M., Sonveaux, P., Pastoreková, S., & Švastová, E. (2017) · Oncotarget · doi:10.18632/oncotarget.20836 · Cited by 40 · see citing works
Hypoxia‐Inducible Factor 1 Inhibitors
Melillo, G. (2007) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(07)35020-9 · Cited by 39 · see citing works
Dimova, E. Y., Michiels, C., & Kietzmann, T. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209789649358 · Cited by 37 · see citing works
Henríquez, J. A., Sleeman, J. P., & Garvalov, B. K. (2018) · Clinical & Experimental Metastasis · doi:10.1007/s10585-018-9930-x · Cited by 37 · see citing works
Hatzimichael, E. C., Dranitsaris, G., Dasoula, A., Benetatos, L., Stebbing, J., Crook, T., & Bourantas, K. L. (2009) · Clinical Lymphoma & Myeloma · doi:10.3816/clm.2009.n.047 · Cited by 36 · see citing works
Kang, M. J., Jung, S. M., Kim, M. J., Bae, J. H., Kim, H. B., Kim, J. Y., Park, S. J., Song, H. S., Kim, D. W., Kang, C., et al. (2008) · FEBS Journal · doi:10.1111/j.1742-4658.2008.06725.x · Cited by 36 · see citing works
CITED2 mediates the paradoxical responses of HIF-1α to proteasome inhibition
Shin, D. H., Li, S., Chun, Y.-S., Huang, E. L., Kim, M.-S., & Park, J.-W. (2007) · Oncogene · doi:10.1038/sj.onc.1210826 · Cited by 35 · see citing works
Papageorgiou, A., Kamat, A. M., Benedict, W. F., Dinney, C. P., & McConkey, D. J. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0474 · Cited by 35 · see citing works
The hypoxic response and aging
Kaeberlein, M. R., & Kapahi, P. (2009) · Cell Cycle · doi:10.4161/cc.8.15.9126 · Cited by 36 · see citing works
Breakthrough science: hypoxia-inducible factors, oxygen sensing, and disorders of hematopoiesis
Semenza, G. L. (2021) · Blood · doi:10.1182/blood.2021011043 · Cited by 35 · see citing works
Sulfonamides as a new scaffold for hypoxia inducible factor pathway inhibitors
Tan, C., de Noronha, R. G., Devi, N. S., Jabbar, A. A., Kaluz, Š., Liu, Y., Mooring, S. R., Nicolaou, K. C., Wang, B., & Meir, E. G. V. (2011) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2011.06.099 · Cited by 34 · see citing works
Bousquet, M. S., Ma, J., Ratnayake, R., Havre, P. A., Yao, J. G., Dang, N. H., Paul, V. J., Carney, T. J., Dang, L. H., & Luesch, H. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.5b00860 · Cited by 32 · see citing works
Bortezomib attenuates HIF-1- but not HIF-2-mediated transcriptional activation
ABD-AZIZ, N., STANBRIDGE, E. J., & SHAFEE, N. (2015) · Oncology Letters · doi:10.3892/ol.2015.3545 · Cited by 31 · see citing works
Self-citationHypoxia-inducible factors: Crosstalk between their protein stability and protein degradation
Wei, W., & Yu, X. D. (2007) · Cancer Letters · doi:10.1016/j.canlet.2007.08.009 · Cited by 31 · see citing works
Kaluz, Š., Kaluzová, M., & Stanbridge, E. J. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21644 · Cited by 27 · see citing works
Self-citationInterplay between receptor tyrosine kinases and hypoxia signaling in cancer
Glück, A. A., Aebersold, D. M., Zimmer, Y., & Medová, M. (2015) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2015.02.018 · Cited by 26 · see citing works
Hsu, C.-W., Huang, R., Khuc, T., Shou, D., Bullock, J., Grooby, S., Griffin, S., Zou, C., Little, A. S., Astley, H. M., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.6995 · Cited by 26 · see citing works
Mittal, K., Choi, D. H., Ogden, A., Donthamsetty, S., Melton, B. D., Gupta, M. V., Pannu, V., Cantuaria, G. H., Varambally, S., Reid, M. D., et al. (2017) · Scientific Reports · doi:10.1038/srep43984 · Cited by 24 · see citing works
Vavilala, D. T., Ponnaluri, V. K. C., Kanjilal, D., & Mukherji, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113717 · Cited by 24 · see citing works
Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53
Abd-Aziz, N., Stanbridge, E. J., & Shafee, N. (2016) · Journal of General Virology · doi:10.1099/jgv.0.000623 · Cited by 21 · see citing works
Self-citationThe hypoxic microenvironment: A determinant of cancer stem cell evolution
Carnero, A., & LLeonart, M. E. (2015) · Inside the Cell · doi:10.1002/icl3.1039 · Cited by 21 · see citing works
Dynamics of the Hypoxia-inducible Factor-1-Vascular Endothelial Growth Factor Promoter Complex*
Yu, P., & Kodadek, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m707557200 · Cited by 19 · see citing works
Wei, J., Yang, Y., Li, Y., Mo, X., Guo, X., Zhang, X., Xu, X., Jiang, Z., & You, Q. (2016) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2016.06.021 · Cited by 18 · see citing works
Vinaiphat, A., Low, J. K., Yeoh, K. W., Chng, W. J., & Sze, S. K. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.559822 · Cited by 18 · see citing works
An analysis of the safety profile of proteasome inhibitors for treating various cancers
Wang, H., Guan, F., Chen, D., Dou, Q. P., & Yang, H. (2014) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2014.939953 · Cited by 18 · see citing works
Shi, Q., Yin, S., Kaluz, Š., Ni, N., Devi, N. S., Mun, J.-Y., Wang, D., Damera, K., Chen, W., Zingales, S. K., et al. (2012) · ACS Medicinal Chemistry Letters · doi:10.1021/ml300042k · Cited by 17 · see citing works
Therapeutic Strategies to Block the Hypoxic Response
DiGiacomo, J. W., & Gilkes, D. M. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12734-3_10 · Cited by 16 · see citing works
The Bmi‐1/NF‐κB/VEGF story: another hint for proteasome involvement in glioma angiogenesis?
Vlachostergios, P. J., & Papandreou, C. N. (2013) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-013-0198-2 · Cited by 14 · see citing works
Silswal, N., Reis, J. C., Qureshi, A. A., Papasian, C. J., & Qureshi, N. (2016) · Shock · doi:10.1097/shk.0000000000000743 · Cited by 13 · see citing works
Kuo, C., Lu, S.-R., Chen, W., Wang, J.-Y., Lee, S., Chang, H., Wo, A. M., Chen, B. P. C., & Lee, H. (2018) · Lab on a Chip · doi:10.1039/c8lc00423d · Cited by 11 · see citing works
Koido, M., Haga, N., Furuno, A., Tsukahara, S., Sakurai, J., Tani, Y., Sato, S., & Tomida, A. (2017) · Oncotarget · doi:10.18632/oncotarget.14415 · Cited by 10 · see citing works
Jensen, C. C., & Warfel, N. A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00039-6 · Cited by 5 · see citing works
Combination Strategies Targeting Hypoxia Inducible Factor 1 (HIF-1) for Cancer Therapy
Rapisarda, A., & Melillo, G. (2010) · Springer eBooks · doi:10.1007/978-1-4419-6615-5_1 · Cited by 5 · see citing works
Comment on the role of FIH in the inhibitory effect of bortezomib on hypoxia-inducible factor-1
Kaluz, Š., Kaluzová, M., & Stanbridge, E. J. (2008) · Blood · doi:10.1182/blood-2008-02-140079 · Cited by 5 · see citing works
Self-citationLee, S.-Y., Mustafa, S., Ching, Y., & Shafee, N. (2017) · Molecular Biology · doi:10.7868/s0026898417010116 · Cited by 4 · see citing works
Lee, S.-Y., Mustafa, S., Ching, Y., & Shafee, N. (2017) · Molecular Biology · doi:10.1134/s0026893317010113 · Cited by 4 · see citing works
HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3 · see citing works
“Paradoxically, bortezomib, a clinically approved proteasome inhibitor used in multiple myeloma, has been repeatedly associated with suppression of HIF-1 signaling, despite the expectation that proteasome inhibition would stabilize HIF-α subunits [336 – 338].”
Uśpieński, T., & Niewiadomski, P. (2024) · Cells · doi:10.3390/cells13171496 · Cited by 3 · see citing works
HIF-1-regulated glucose metabolism in the control of apoptosis signaling
Fulda, S. (2008) · Expert Review of Endocrinology & Metabolism · doi:10.1586/17446651.3.3.303 · Cited by 3 · see citing works
Exploiting “Hif Addiction” For Cancer Therapy
Fer, N. D., & Rapisarda, A. (2013) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-1-4614-9167-5_14 · Cited by 2 · see citing works
Gastric Cancer: Overexpression of Hypoxia-Inducible Factor 1 as a Prognostic Factor
Kakeji, Y., Oki, E., Sadanaga, N., Morita, M., & Maehara, Y. (2008) · Springer eBooks · doi:10.1007/978-1-4020-8900-8_17 · Cited by 1 · see citing works
- Authors
- Kaluz, S., Kaluzová, M., & Stanbridge, E. J.
- Affiliations
- Department of Microbiology and Molecular Genetics, College of Medicine, University of California at Irvine
- University of California, Irvine (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-08-01
- Volume
- 26
- Issue
- 15
- Pages
- 5895-5907
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2103794392
- Cited by
- 108
- References
- 64
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 5 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 8 · 2016: 8 · 2015: 9 · 2014: 7 · 2013: 5 · 2012: 8
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Open access
- green
- escholarship.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Avon Foundation for Women
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- proteasome inhibition, HIF-1α, HIF-1, ubiquitin-proteasome system, C-terminal activation domain, carbonic anhydrase IX, vascular endothelial growth factor, P300, transcriptional regulation, anticancer activity
- MeSH terms
- Bortezomib, Animals, Hypoxia, Boronic Acids, Carbonic Anhydrases, Cell Line, Enzyme Activation, Gene Expression Regulation, Humans, Isoenzymes, Protease Inhibitors, Pyrazines, Recombinant Fusion Proteins, Transcription, Genetic, Biomarkers, Protein Structure, Tertiary, Vascular Endothelial Growth Factor A, Proteasome Endopeptidase Complex, p300-CBP Transcription Factors, Hypoxia-Inducible Factor 1, alpha Subunit, Proteasome Inhibitors
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