Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer
Open accessAbstract
The antidiabetic drug metformin exhibits both chemopreventive and chemotherapeutic activity for multiple cancers including pancreatic cancer; however, the underlying mechanism of action of metformin is unclear. A recent study showed that metformin down-regulated specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells and tumors, and this was accompanied by down-regulation of several pro-oncogenic Sp-regulated genes. Treatment with metformin or down-regulation of Sp TFs by RNAi also inhibits two major pro-oncogenic pathways in pancreatic cancer cells, namely mammalian target of rapamycin (mTOR) signaling and epidermal growth factor (EGFR)-dependent activation of Ras. Metformin and Sp knockdown by RNAi decreased expression of the insulin-like growth factor-1 receptor (IGF-1R), resulting in inhibition of mTOR signaling. Ras activity was also decreased by metformin and Sp knockdown of EGFR, another Sp-regulated gene. Thus, the antineoplastic activities of metformin in pancreatic cancer are due, in part, to down-regulation of Sp TFs and Sp-regulated IGF-1R and EGFR, which in turn results in inhibition of mTOR and Ras signaling, respectively.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Many in vitro studies have used mM concentrations of metformin to demonstrate an anti-proliferative action in tumor cells in culture.
“However, many in vitro studies have used mM concentrations of metformin to demonstrate an anti-proliferative action in tumor cells in culture [see (114, 115); Table 2].”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [114]
Beneficial effects of metformin are not seen in all cancers.
“In conclusion, since beneficial effects of metformin are not seen in all cancers further studies are required to determine whether the anti-cancer actions are direct or are secondary to the positive effects of metformin on healthspan that are apparent in obese patients such as improved glucose homeostasis, enhanced insulin sensitivity and reduced signaling through the IGF-1–mTOR pathway (114, 242)”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [114]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo
Zou, M., Kirkpatrick, S. S., Davis, B. J., Nelson, J. S., Wiles, W. G., Schlattner, U., Neumann, D., Brownlee, M., Freeman, M. B., & Goldman, M. H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404421200 · Cited by 471 · see citing works
RetractedMetformin and reduced risk of cancer in diabetic patients
Evans, J. M. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., & Morris, A. D. (2005) · BMJ · doi:10.1136/bmj.38415.708634.f7 · Cited by 2,388 · see citing works
The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., & Cantley, L. C. (2005) · Science · doi:10.1126/science.1120781 · Cited by 1,950 · see citing works
SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth
Porstmann, T., Santos, C. R., Griffiths, B., Cully, M., Wu, M., Leevers, S., Griffiths, J. R., Chung, Y.-L., & Schulze, A. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.07.007 · Cited by 1,413 · see citing works
New Users of Metformin Are at Low Risk of Incident Cancer
Libby, G., Donnelly, L. A., Donnan, P. T., Alessi, D. R., Morris, A. D., & Evans, J. M. M. (2009) · Diabetes Care · doi:10.2337/dc08-2175 · Cited by 996 · see citing works
Buzzai, M., Jones, R. G., Amaravadi, R. K., Lum, J. J., DeBerardinis, R. J., Zhao, F., Viollet, B., & Thompson, C. B. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4447 · Cited by 923 · see citing works
Jiralerspong, S., Palla, S. L., Giordano, S. H., Meric-Bernstam, F., Liedtke, C., Barnett, C. M., Hsu, L., Hung, M.-C., Hortobagyi, G. N., & Gonzalez-Angulo, A. M. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.19.6410 · Cited by 880 · see citing works
Sahra, I. B., Laurent, K., Loubat, A., Giorgetti-Peraldi, S., Colosetti, P., Auberger, P., Tanti, J. F., Le Marchand-Brustel, Y., & Bost, F. (2008) · Oncogene · doi:10.1038/sj.onc.1211024 · Cited by 861 · see citing works
Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1
Ben Sahra, I., Regazzetti, C., Robert, G., Laurent, K., Le Marchand-Brustel, Y., Auberger, P., Tanti, J.-F., Giorgetti-Peraldi, S., & Bost, F. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-1769 · Cited by 616 · see citing works
EGF Receptor is Required for KRAS-induced Pancreatic Tumorigenesis
Ardito, C. M., Grüner, B., Takeuchi, K. K., Lubeseder-Martellato, C., Teichmann, N., Mazur, P., DelGiorno, K. E., Carpenter, E. S., Halbrook, C., Hall, J. C., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.07.024 · Cited by 522 · see citing works
Metformin in cancer therapy: a new perspective for an old antidiabetic drug?
Ben Sahra, I., Le Marchand-Brustel, Y., Tanti, J.-F., & Bost, F. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-1186 · Cited by 493 · see citing works
Furuta, E., Pai, S. K., Zhan, R., Bandyopadhyay, S., Watabe, M., Mo, Y., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-2489 · Cited by 392 · see citing works
EGF Receptor Signaling Is Essential for K-Ras Oncogene-Driven Pancreatic Ductal Adenocarcinoma
Navas, C., Hernández-Porras, I., Schuhmacher, A. J., Sibilia, M., Guerra, C., & Barbacid, M. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.08.001 · Cited by 391 · cited 4× · see citing works
“5A), and this is consistent with the role of the EGFR-Ras pathway in pancreatic cancer cell proliferation (37, 38).”
BackgroundInfluentialMetformin in cancer: translational challenges
Dowling, R. J. O., Niraula, S., Stambolic, V., & Goodwin, P. J. (2012) · Journal of Molecular Endocrinology · doi:10.1530/jme-12-0007 · Cited by 357 · see citing works
Kisfalvi, K., Eibl, G., Sinnett‐Smith, J. W., & Rozengurt, E. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0418 · Cited by 315 · see citing works
Metformin Use Is Associated with Better Survival of Diabetic Patients with Pancreatic Cancer
Sadeghi, N., Abbruzzese, J. L., Yeung, S. J., Hassan, M. M., & Li, D. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2994 · Cited by 306 · see citing works
Bergmann, U., Funatomi, H., Yokoyama, M., Beger, H. G., & Korc, M. (1995) · PubMed · Cited by 304 · see citing works
Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase
Owen, J., Zhang, Y., Bae, S., Farooqi, M., Liang, G., Hammer, R., Goldstein, J., & Brown, M. S. (2012) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1213343109 · Cited by 276 · see citing works
Wright, J. L., & Stanford, J. L. (2009) · Cancer Causes & Control · doi:10.1007/s10552-009-9407-y · Cited by 276 · see citing works
Storozhuk, Y., Hopmans, S., Sanli, T., Barron, C. C., Tsiani, E., Cutz, J.-C., Pond, G. R., Wright, J. R., Singh, G., & Tsakiridis, T. K. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.187 · Cited by 272 · see citing works
In vitro metformin anti-neoplastic activity in epithelial ovarian cancer
Gotlieb, W. H., Saumet, J., Beauchamp, M.-C., Gu, J., Lau, S. K., Pollak, M., & Bruchim, I. (2008) · Gynecologic Oncology · doi:10.1016/j.ygyno.2008.04.008 · Cited by 267 · see citing works
Rozengurt, E., Sinnett-Smith, J., & Kisfalvi, K. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-2229 · Cited by 247 · cited 6× · see citing works
“The potential clinical applications for metformin in cancer chemotherapy also stems from reports on the anticancer activities of this drug in cancer cells in culture and in in vivo models (1-4,13-28).”
BackgroundInfluentialMetformin and Other Biguanides in Oncology: Advancing the Research Agenda
Pollak, M. (2010) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-10-0175 · Cited by 240 · cited 2× · see citing works
“The potential clinical applications for metformin in cancer chemotherapy also stems from reports on the anticancer activities of this drug in cancer cells in culture and in in vivo models (1-4,13-28).”
BackgroundMetformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner
Cerezo, M., Tichet, M., Abbe, P., Ohanna, M., Lehraiki, A., Rouaud, F., Allégra, M., Giacchero, D., Bahadoran, P., Bertolotto, C., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-1226-t · Cited by 223 · see citing works
Abdelrahim, M., Smith, R., Burghardt, R. C., & Safe, S. H. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0713 · Cited by 199 · see citing works
Self-citationJutooru, I., Chadalapaka, G., Lei, P., & Safe, S. H. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.095240 · Cited by 178 · see citing works
Self-citationKim, H. G., Hiền, T. T., Han, E. H., Hwang, Y. P., Choi, J. H., Kang, K. W., Kwon, K., Kim, B., Kim, S. K., Song, G., et al. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01101.x · Cited by 172 · see citing works
Sp1, a New Biomarker That Identifies a Subset of Aggressive Pancreatic Ductal Adenocarcinoma
Jiang, N. Y., Woda, B. A., Banner, B. F., Whalen, G. F., Dresser, K., & Lü, D. (2008) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-07-2791 · Cited by 159 · see citing works
Metformin induces apoptosis of pancreatic cancer cells
Wang, L., Li, Z., Zou, D., Jin, Z., Gao, J., & Xu, G.-M. (2008) · World Journal of Gastroenterology · doi:10.3748/wjg.14.7192 · Cited by 153 · see citing works
Garrett, C. R., Hassabo, H. M., Bhadkamkar, N. A., Wen, S., Baladandayuthapani, V., Kee, B. K., Eng, C., & Hassan, M. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.71 · Cited by 151 · see citing works
Yasmeen, A., Beauchamp, M.-C., Piura, E., Segal, E., Pollak, M., & Gotlieb, W. H. (2011) · Gynecologic Oncology · doi:10.1016/j.ygyno.2011.02.021 · Cited by 132 · see citing works
Tan, B. K., Adya, R., Chen, J., Lehnert, H., Cassia, L. J. S., & Randeva, H. S. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-1803 · Cited by 129 · see citing works
Karnevi, E., Hilmersson, K. S., Andersson, R. E., & Rosendahl, A. H. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-235 · Cited by 128 · see citing works
Johnson, A., Ishii, S., Jinno, Y., Pastan, I. H., & Merlino, G. T. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)60621-0 · Cited by 125 · see citing works
Soares, H. P., Ni, Y., Kisfalvi, K., Sinnett‐Smith, J. W., & Rozengurt, E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057289 · Cited by 124 · see citing works
Gou, S., Cui, P., Li, X., Shi, P., Liu, T., & Wang, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063969 · Cited by 109 · see citing works
Zhuang, Y., & Miskimins, W. K. (2011) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-10-0343 · Cited by 109 · see citing works
Jutooru, I., Guthrie, A. S., Chadalapaka, G., Pathi, S. S., Kim, K., Burghardt, R. C., Jin, U.-H., & Safe, S. H. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01602-13 · Cited by 108 · see citing works
Self-citationAbdelrahim, M., Baker, C. H., Abbruzzese, J. L., Sheikh‐Hamad, D., Liu, S., Cho, S. D., Yoon, K., & Safe, S. H. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3831 · Cited by 107 · see citing works
Self-citationSinnett‐Smith, J. W., Kisfalvi, K., Kui, R. K., & Rozengurt, E. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.11.010 · Cited by 106 · see citing works
Antidiabetic Medication and Prostate Cancer Risk: A Population-based Case-Control Study
Murtola, T. J., Tammela, T. L. J., Lahtela, J. T., & Auvinen, A. P. (2008) · American Journal of Epidemiology · doi:10.1093/aje/kwn190 · Cited by 104 · see citing works
Overexpression of Sp1 transcription factor induces apoptosis
Deniaud, E., Baguet, J., Mathieu, A., Pagès, G., Marvel, J., & Leverrier, Y. (2006) · Oncogene · doi:10.1038/sj.onc.1209696 · Cited by 100 · see citing works
Nair, V., Pathi, S. S., Jutooru, I., Sreevalsan, S., Basha, R. M., Abdelrahim, M., Samudio, I. J., & Safe, S. H. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt231 · Cited by 100 · see citing works
Self-citationChadalapaka, G., Jutooru, I., Burghardt, R. C., & Safe, S. H. (2010) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-09-0493 · Cited by 98 · see citing works
Self-citationJutooru, I., Chadalapaka, G., Abdelrahim, M., Basha, R. M., Samudio, I. J., Konopleva, M. Y., Andreeff, M., & Safe, S. H. (2010) · Molecular Pharmacology · doi:10.1124/mol.110.064451 · Cited by 92 · see citing works
Self-citationSp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells
Lü, S., & Archer, M. C. (2009) · International Journal of Cancer · doi:10.1002/ijc.24761 · Cited by 91 · see citing works
A Cohort Study of Metformin Exposure and Survival in Patients with Stage I–III Colorectal Cancer
Spillane, S., Bennett, K., Sharp, L., & Barron, T. I. (2013) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-13-0347 · Cited by 90 · see citing works
Beitner‐Johnson, D., Werner, H., Roberts, C. T., & LeRoith, D. (1995) · Molecular Endocrinology · doi:10.1210/mend.9.9.7491107 · Cited by 85 · see citing works
Chemoprevention Meets Glucose Control
Engelman, J. A., & Cantley, L. C. (2010) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-10-0178 · Cited by 58 · see citing works
Sreevalsan, S., & Safe, S. H. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0486 · Cited by 31 · see citing works
Self-citation
Flagged first, then by citations
1 of the 51 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Metformin as a tool to target aging
Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.011 · Cited by 1,096 · see citing works
Aging and age‐related diseases: from mechanisms to therapeutic strategies
Li, Z., Zhang, Z., Ren, Y., Wang, Y., Fang, J., Yue, H., Ma, S., & Guan, F. (2021) · Biogerontology · doi:10.1007/s10522-021-09910-5 · Cited by 668 · see citing works
Madeo, F., Carmona-Gutierrez, D., Hofer, S. J., & Kroemer, G. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.018 · Cited by 630 · see citing works
Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy., K. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.08.003 · Cited by 455 · see citing works
Sp1 transcription factor: A long-standing target in cancer chemotherapy
Vizcaíno, C., Mansilla, S., & Portugal, J. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.05.008 · Cited by 437 · see citing works
Justice, J. N., Ferrucci, L., Newman, A. B., Aroda, V. R., Bahnson, J. L., Divers, J., Espeland, M. A., Marcovina, S., Pollak, M. N., Kritchevsky, S. B., et al. (2018) · GeroScience · doi:10.1007/s11357-018-0042-y · Cited by 359 · see citing works
Metformin: a review of its potential indications
Wang, Y., He, S., Feng, X., Cheng, J. Q., Luo, Y.-T., Tian, L., & Huang, Q. (2017) · Drug Design Development and Therapy · doi:10.2147/dddt.s141675 · Cited by 324 · see citing works
Mohammed, I., Hollenberg, M. D., Ding, H., & Triggle, C. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.718942 · Cited by 278 · see citing works
Role of AMPK mediated pathways in autophagy and aging
Ge, Y., Zhou, M., Chen, C., Wu, X., & Wang, X. (2021) · Biochimie · doi:10.1016/j.biochi.2021.11.008 · Cited by 253 · see citing works
Obesity and aging: Molecular mechanisms and therapeutic approaches
Santos, A. L., & Sinha, S. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101268 · Cited by 240 · see citing works
Reni, M., Dugnani, E., Cereda, S., Belli, C., Balzano, G., Nicoletti, R., Liberati, D., Pasquale, V., Scavini, M., Maggiora, P. M., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1722 · Cited by 173 · see citing works
Lin, Y.-H., Wu, M., Huang, Y., Yeh, C., Cheng, M., Chi, H., Tsai, C., Chung, I., Chen, C., & Lin, K. (2017) · Hepatology · doi:10.1002/hep.29462 · Cited by 171 · see citing works
Kunisada, Y., Eikawa, S., Tomonobu, N., Domae, S., Uehara, T., Hori, S., Furusawa, Y., Hase, K., Sasaki, A., & Udono, H. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.10.009 · Cited by 150 · see citing works
Aging and Caloric Restriction Research: A Biological Perspective with Translational Potential
Balasubramanian, P., Howell, P. R., & Anderson, R. M. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.06.015 · Cited by 148 · see citing works
Incio, J., Suboj, P., Chin, S. M., Vardam-Kaur, T., Liu, H., Hato, T., Babykutty, S., Chen, I. X., Deshpande, V., Jain, R. K., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0141392 · Cited by 142 · see citing works
Anticancer mechanisms of metformin: A review of the current evidence
Zhao, B., Luo, J., Yu, T., Zhou, L., Lv, H., & Shang, P. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117717 · Cited by 124 · see citing works
Specificity Protein Transcription Factors and Cancer: Opportunities for Drug Development
Safe, S. H., Abbruzzese, J. L., Abdelrahim, M., & Hedrick, E. (2018) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-17-0407 · Cited by 120 · see citing works
Self-citationSP and KLF Transcription Factors in Digestive Physiology and Diseases
Kim, C.-K., He, P., Bialkowska, A. B., & Yang, V. W. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.03.035 · Cited by 114 · see citing works
The double-edged sword of AMPK signaling in cancer and its therapeutic implications
Jeon, S., & Hay, N. (2015) · Archives of Pharmacal Research · doi:10.1007/s12272-015-0549-z · Cited by 115 · see citing works
Towards natural mimetics of metformin and rapamycin
Aliper, A. M., Jellen, L. C., Cortese, F., Artemov, A. V., Karpinsky‐Semper, D., Moskalev, A., Swick, A. G., & Zhavoronkov, A. A. (2017) · Aging · doi:10.18632/aging.101319 · Cited by 111 · see citing works
A Rising Star in Pancreatic Diseases: Pancreatic Stellate Cells
Xue, R., Jia, K., Wang, J., Yang, L., Wang, Y., Gao, L., & Hao, J. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00754 · Cited by 112 · see citing works
Sharma, P., & Kumar, S. (2018) · Cellular Oncology · doi:10.1007/s13402-018-0398-0 · Cited by 102 · see citing works
Liu, F., Yan, L., Wang, Z., Lu, Y., Chu, Y., Li, X., Liu, Y., Rui, D., Nie, S., & Xiang, H. (2017) · Oncotarget · doi:10.18632/oncotarget.13762 · Cited by 99 · see citing works
Hedrick, E., Cheng, Y., Jin, U.-H., Kim, K., & Safe, S. H. (2016) · Oncotarget · doi:10.18632/oncotarget.7925 · Cited by 99 · see citing works
Self-citationCurrent nutritional and pharmacological anti-aging interventions
Ros, M., & Carrascosa, J. M. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.165612 · Cited by 95 · see citing works
Oaks, Z., Winans, T., Huang, N., Bánki, K., & Perl, A. (2016) · Current Rheumatology Reports · doi:10.1007/s11926-016-0622-8 · Cited by 93 · see citing works
Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment
Sui, X., Xu, Y., Wang, X., Han, W., Pan, H., & Xiao, M. (2015) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.5b00577 · Cited by 91 · see citing works
Dissecting the role of AMP-activated protein kinase in human diseases
Li, J., Zhong, L., Wang, F., & Zhu, H. (2017) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2016.12.003 · Cited by 89 · see citing works
Pleiotropic Effects of Metformin on Cancer
Schulten, H.-J. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102850 · Cited by 86 · see citing works
Dysregulations in the PI3K pathway and targeted therapies for head and neck squamous cell carcinoma
Cai, Y., Dodhia, S., & Su, G. H. (2017) · Oncotarget · doi:10.18632/oncotarget.14729 · Cited by 86 · see citing works
Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits
Böhme, J., Martínez, N., Li, S., Lee, A., Marzuki, M., Tizazu, A. M., Ackart, D. F., Haugen, J. D., Todd, A., Lachmandas, E., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19095-z · Cited by 81 · see citing works
Cifarelli, V., Lashinger, L. M., Devlin, K. L., Dunlap, S. M., Huang, J. C., Kaaks, R., Pollak, M., & Hursting, S. D. (2015) · Diabetes · doi:10.2337/db14-1132 · Cited by 80 · see citing works
Metformin and Breast Cancer: Molecular Targets
Faria, J., Negalha, G. D. C., Azevedo, A., & Martel, F. (2019) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1007/s10911-019-09429-z · Cited by 75 · see citing works
Chai, X.-Q., Chu, H., Yang, X., Meng, Y.-P., Shi, P., & Gou, S. (2015) · Scientific Reports · doi:10.1038/srep14404 · Cited by 74 · see citing works
Obesity and Cancer: An Angiogenic and Inflammatory Link
Fukumura, D., Incio, J., Shankaraiah, R. C., & Jain, R. K. (2016) · Microcirculation · doi:10.1111/micc.12270 · Cited by 69 · see citing works
Diabetes, pancreatic cancer, and metformin therapy
Gong, J., Robbins, L., Lugea, A., Waldron, R. T., Jeon, C. Y., & Pandol, S. J. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00426 · Cited by 67 · see citing works
Jian‐Yu, E., Graber, J. M., Lu, S., Lin, Y., Lu‐Yao, G. L., & Tan, X. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867324666170412145232 · Cited by 67 · see citing works
Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy
Vidoni, C., Ferraresi, A., Esposito, A., Maheshwari, C., Dhanasekaran, D. N., Mollace, V., & Isidoro, C. (2021) · Journal of Cancer Prevention · doi:10.15430/jcp.2021.26.4.224 · Cited by 67 · see citing works
Ochoa-González, F. D. L., Cervantes-Villagrana, A. R., Fernández-Ruiz, J. C., Nava-Ramirez, H. S., Hernandez-Correa, A. C., Enciso‐Moreno, J. A., & Castañeda‐Delgado, J. E. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150900 · Cited by 63 · see citing works
Metformin-induced anticancer activities: recent insights
Safe, S. H., Nair, V., & Karki, K. (2017) · Biological Chemistry · doi:10.1515/hsz-2017-0271 · Cited by 61 · see citing works
Self-citationSp1-mediated transcriptional regulation of MALAT1 plays a critical role in tumor
Li, S., Wang, Q., Qiang, Q., Shan, H., Shi, M., Chen, B., Zhao, S., & Yuan, L. (2015) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-015-1951-0 · Cited by 62 · see citing works
Miricescu, D., Bădoiu, S. C., Stănescu-Spînu, I.-I., Totan, A., Ștefani, C., & Greabu, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179512 · Cited by 62 · see citing works
Metformin: A Dual-Role Player in Cancer Treatment and Prevention
Galal, M. A., Al-Rimawi, M., Hajeer, A., Dahman, H., Alouch, S. S., & Aljada, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25074083 · Cited by 68 · see citing works
You, R., Wang, B., Chen, P., Zheng, X., Hou, D., Wang, X., Zhang, B., Chen, L., Li, D., Lin, X., et al. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215582 · Cited by 56 · see citing works
Kawakita, E., Yang, F., Kumagai, A., Takagaki, Y., Kitada, M., Yoshitomi, Y., Ikeda, T., Nakamura, Y., Ishigaki, Y., Kanasaki, K., et al. (2020) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-20-0115 · Cited by 57 · see citing works
Gong, J., Kelekar, G., Shen, J., Shen, J., Kaur, S., & Mita, M. M. (2016) · Targeted Oncology · doi:10.1007/s11523-016-0423-z · Cited by 55 · see citing works
Menthol in electronic cigarettes: A contributor to respiratory disease?
Nair, V., Tran, M., Behar, R. Z., Zhai, S., Cui, X., Phandthong, R., Wang, Y., Pan, S., Luo, W., Pankow, J. F., et al. (2020) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2020.115238 · Cited by 53 · see citing works
Self-citationSpecificity Proteins (Sp) and Cancer
Safe, S. H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065164 · Cited by 53 · see citing works
Self-citationCaloric restriction induced epigenetic effects on aging
Zhai, J., Kongsberg, W. H., Pan, Y., Hao, C., Wang, X., & Sun, J. Y. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1079920 · Cited by 55 · see citing works
Chen, X., Walther, F. J., Sengers, R. M. A., Laghmani, E. H., Salam, A., Folkerts, G., Pera, T., & Wagenaar, G. T. M. (2015) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00389.2014 · Cited by 51 · see citing works
Metformin and cancer: Between the bioenergetic disturbances and the antifolate activity
Jara, J. A., & López‐Muñoz, R. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.06.014 · Cited by 50 · see citing works
Metformin: review of epidemiology and mechanisms of action in pancreatic cancer
Eibl, G., & Rozengurt, E. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-09977-z · Cited by 49 · see citing works
Kim, N., Lee, H., & Lee, C. (2015) · International Journal of Oncology · doi:10.3892/ijo.2015.3004 · Cited by 45 · see citing works
Yue, W., Wang, T., Zachariah, E., Lin, Y., Yang, C. S., Xu, Q., DiPaola, R. S., & Tan, X. (2015) · Scientific Reports · doi:10.1038/srep13390 · Cited by 43 · see citing works
Hart, T. D., Dider, S., Han, W., Xu, H., Zhao, Z., & Xie, L. (2016) · Scientific Reports · doi:10.1038/srep20441 · Cited by 44 · see citing works
Wu, L., Cen, Y., Feng, M., Zhou, Y., Tang, H. J., Liao, X., Wang, Y., Wang, M., & Zhou, M. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/1709718 · Cited by 41 · see citing works
Metformin and cognition from the perspectives of sex, age, and disease
Chaudhari, K., Reynolds, C. D., & Yang, S.-H. (2020) · GeroScience · doi:10.1007/s11357-019-00146-3 · Cited by 41 · see citing works
Repurposing metformin for the treatment of gastrointestinal cancer
Júnior, A. D. D. C., Bragagnoli, A. S. C., Costa, F. O., & Carvalheira, J. B. C. (2021) · World Journal of Gastroenterology · doi:10.3748/wjg.v27.i17.1883 · Cited by 42 · see citing works
De Lellis, L., Veschi, S., Tinari, N., Mokini, Z., Carradori, S., Brocco, D., Florio, R., Grassadonia, A., & Cama, A. (2021) · Cancers · doi:10.3390/cancers13163946 · Cited by 40 · see citing works
Nurcahyanti, A. D. R., Jap, A., Lady, J., Prismawan, D., Sharopov, F. S., Daoud, R., Wink, M., & Sobeh, M. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112138 · Cited by 39 · see citing works
Andersen, H. B., Ialchina, R., Pedersen, S. F., & Czaplińska, D. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-10004-4 · Cited by 40 · see citing works
Physiological Systems in Promoting Frailty
Perazza, L. R., Brown‐Borg, H. M., & Thompson, L. V. (2022) · Comprehensive physiology · doi:10.1002/cphy.c210034 · Cited by 64 · see citing works
Ambe, C. M., Mahipal, A., Fulp, J., Chen, L., & Malafa, M. P. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151632 · Cited by 39 · see citing works
The Cutting Edge: The Role of mTOR Signaling in Laminopathies
Chiarini, F., Evangelisti, C., Cenni, V., Fazio, A., Paganelli, F., Martelli, A. M., & Lattanzi, G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20040847 · Cited by 35 · see citing works
Teissier, T., Temkin, V., Pollak, R. D., & Cox, L. S. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.812157 · Cited by 35 · see citing works
Bhaw‐Luximon, A., & Jhurry, D. (2016) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-016-2178-4 · Cited by 34 · see citing works
Altered steady state and activity-dependent de novo protein expression in fragile X syndrome
Bowling, H. L., Bhattacharya, A., Zhang, G., Alam, D. H., Lebowitz, J. Z., Bohm-Levine, N., Lin, D., Singha, P., Mamcarz, M., Puckett, R. E., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09553-8 · Cited by 33 · see citing works
Molecular inhibition of RAS signalling to target ageing and age-related health
Laskovs, M., Partridge, L., & Slack, C. (2022) · Disease Models & Mechanisms · doi:10.1242/dmm.049627 · Cited by 31 · see citing works
Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review
Zhang, Y., Zhou, F., Guan, J., Zhou, L., & Chen, B. (2023) · Biomolecules · doi:10.3390/biom13020250 · Cited by 34 · see citing works
Physiological Systems in Promoting Frailty
Perazza, L. R., Brown‐Borg, H. M., & Thompson, L. V. (2022) · Comprehensive physiology · doi:10.1002/j.2040-4603.2022.tb00224.x · Cited by 30 · see citing works
Metformin enhances radiation response of ECa109 cells through activation of ATM and AMPK
Feng, T., Li, L., Ling, S., Fan, N., Fang, M., Zhang, H., Fang, X. H., Lan, W., Hou, Z., Meng, Q.-C., et al. (2014) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2014.11.021 · Cited by 30 · see citing works
Ward, N. P., Poff, A. M., Koutnik, A. P., & D’Agostino, D. P. (2017) · PLoS ONE · doi:10.1371/journal.pone.0180061 · Cited by 28 · see citing works
TYRO3: A potential therapeutic target in cancer
Hsu, P., Jou, J., & Tsai, S. (2019) · Experimental Biology and Medicine · doi:10.1177/1535370219828195 · Cited by 27 · see citing works
Ivanenko, K. A., Prassolov, V., & Khabusheva, E. (2022) · Molecular Biology · doi:10.1134/s0026893322050089 · Cited by 27 · see citing works
Metformin and Everolimus: A Promising Combination for Neuroendocrine Tumors Treatment
Vitali, E., Boemi, I., Tarantola, G., Piccini, S., Zerbi, A., Veronesi, G., Baldelli, R., Mazziotti, G., Smiroldo, V., Lavezzi, E., et al. (2020) · Cancers · doi:10.3390/cancers12082143 · Cited by 26 · see citing works
Hernandes, C., Miguita, L., de Sales, R. O., Silva, E. D. P., de Mendonça, P. O. R., da Silva, B. L., Klingbeil, M. F. G., Mathor, M. B., Rangel, É. B., Marti, L. C., et al. (2020) · Molecules · doi:10.3390/molecules25030760 · Cited by 22 · see citing works
Therapeutics That Can Potentially Replicate or Augment the Anti-Aging Effects of Physical Exercise
Lages, A. D. S., Lopes, V., Horta, J., Espregueira‐Mendes, J., Andrade, R., & Rebelo‐Marques, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179957 · Cited by 22 · see citing works
Zhang, Q., Lv, L., Ma, P., Zhang, Y., Deng, J., & Zhang, Y. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.743938 · Cited by 22 · see citing works
Effect of metformin on the epigenetic age of peripheral blood in patients with diabetes mellitus
Li, M., Duan, L., 蔡育倫, Hao, B., Chen, J., & Liu, H. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.955835 · Cited by 26 · see citing works
Saxena, S., & Kumar, S. (2020) · GeroScience · doi:10.1007/s11357-020-00167-3 · Cited by 22 · see citing works
Wang, F., Ding, X., Wang, T., Shan, Z., Wang, J., Wu, S., Chi, Y., Zhang, Y., Lv, Z., Wang, L., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0174276 · Cited by 20 · see citing works
Human Aging and Age-Related Diseases: From Underlying Mechanisms to Pro-Longevity Interventions
Chmielewski, P., Data, K., Strzelec, B., Farzaneh, M., Anbiyaiee, A., Zaheer, U., Uddin, S., Sheykhi-Sabzehpoush, M., Mozdziak, P., Zabel, M., et al. (2024) · Aging and Disease · doi:10.14336/ad.2024.0280 · Cited by 16 · see citing works
Safe, S. H. (2024) · Exploration of Drug Science · doi:10.37349/eds.2024.00054 · Cited by 19 · see citing works
Self-citationBever, K. M., Borazanci, E. H., Thompson, E. A., Durham, J. N., Pinero, K., Jameson, G., Vrana, A., Liu, M., Wilt, C., Wu, A. A., et al. (2020) · Oncotarget · doi:10.18632/oncotarget.27586 · Cited by 19 · see citing works
Pharmacological Approaches to Decelerate Aging: A Promising Path
Hassani, B., Goshtasbi, G., Nooraddini, S., & Firouzabadi, N. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/4201533 · Cited by 19 · see citing works
Metformin: A Promising Antidiabetic Medication for Cancer Treatment
Mu, W., Jiang, Y., Liang, G., Feng, Y., & Qu, F. (2022) · Current Drug Targets · doi:10.2174/1389450124666221104094918 · Cited by 18 · see citing works
Jin, K., Ruan, L., Pu, J., Zhong, A., Wang, F., Tan, S., Huang, H., Mu, J., & Yang, G. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.07.007 · Cited by 18 · see citing works
A novel insight into the anticancer mechanism of metformin in pancreatic neuroendocrine tumor cells
Vitali, E., Boemi, I., Piccini, S., Tarantola, G., Smiroldo, V., Lavezzi, E., Brambilla, T., Zerbi, A., Carnaghi, C., Mantovani, G., et al. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110803 · Cited by 18 · see citing works
Saito, Y., Chikenji, T., Ozasa, Y., Fujimiya, M., Yamashita, T., Gingery, A., & Iba, K. (2017) · Scientific Reports · doi:10.1038/s41598-017-16443-w · Cited by 17 · see citing works
Shrestha, R., Mohankumar, K., Jin, U.-H., Martin, G. G., & Safe, S. H. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0474 · Cited by 17 · see citing works
Self-citationŞeylan, C., & Tarhan, Ç. (2023) · FEMS Yeast Research · doi:10.1093/femsyr/foad018 · Cited by 17 · see citing works
Shirooie, S., Sahebgharani, M., Esmaeili, J., & Dehpour, A. R. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27125 · Cited by 17 · see citing works
Beyond diabetes mellitus: role of metformin in non-muscle-invasive bladder cancer
Wang, Z., Ong, W., Shen, T., Sng, J., Lata, R., Mahendran, R., Esuvaranathan, K., & Chiong, E. (2020) · Singapore Medical Journal · doi:10.11622/smedj.2020121 · Cited by 17 · see citing works
Metformin as a disease-modifying therapy in osteoarthritis: bridging metabolism and joint health
Halabitska, I., Petakh, P., & Kamyshnyi, O. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1567544 · Cited by 16 · see citing works
Resistance Training’s Ability to Prevent Cancer-induced Muscle Atrophy Extends Anabolic Stimulus
Padilha, C. S., Cella, P. S., Chimin, P., Voltarelli, F. A., Marinello, P. C., Testa, M. T. D. J., Guirro, P. B., Duarte, J. A., Cecchini, R., Guarnier, F. A., et al. (2021) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002624 · Cited by 16 · see citing works
Hodeib, M., Ogrodzinski, M. P., Vergnes, L., Reue, K., Karlan, B. Y., Lunt, S. Y., & Aspuria, P.-J. P. (2017) · Oncotarget · doi:10.18632/oncotarget.23661 · Cited by 16 · see citing works
Hu, A., Hu, Z., Ye, J., Liu, Y., Lai, Z., Zhang, M., Ji, W., Huang, L., Zou, H., Chen, B., et al. (2022) · Biochemistry and Cell Biology · doi:10.1139/bcb-2021-0409 · Cited by 15 · see citing works
Mahalingam, D., Hanni, S., Serritella, A. V., Fountzilas, C. K., Michalek, J. E., Hernandez, B. S., Sarantopoulos, J., Datta, P., Romero, O., Pillai, S. M. A., et al. (2023) · Oncotarget · doi:10.18632/oncotarget.28458 · Cited by 14 · see citing works
Current trends and future prospects of drug repositioning in gastrointestinal oncology
Fatemi, N., Karimpour, M., Bahrami, H., Zali, M. R., Chaleshi, V., Riccio, A., Mojarad, E. N., & Totonchi, M. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1329244 · Cited by 13 · see citing works
Analysis of Important Gene Ontology Terms and Biological Pathways Related to Pancreatic Cancer
Yin, H., Wang, S., Zhang, Y., Cai, Y., & Liu, H. (2016) · BioMed Research International · doi:10.1155/2016/7861274 · Cited by 13 · see citing works
- Authors
- Nair, V., Sreevalsan, S., Basha, R., Abdelrahim, M., Abudayyeh, A., Rodrigues Hoffman, A., & Safe, S.
- Affiliations
- Texas A&M University (US)
- Baylor College of Medicine (US)
- The University of Texas MD Anderson Cancer Center (US)
- Texas A&M Health Science Center (US)
- Corresponding author
- Safe, Stephen
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 289
- Issue
- 40
- Pages
- 27692-27701
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4183806
- OpenAlex
- W2043152532
- Cited by
- 129
- References
- 51
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 8 · 2022: 11 · 2021: 14 · 2020: 17 · 2019: 10 · 2018: 11 · 2017: 16 · 2016: 13 · 2015: 13 · 2014: 3
- FWCI
- 6.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01CA136571, P30ES023512)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- metformin, pancreatic cancer, mTOR signaling, Ras signaling, specificity protein transcription factors, Sp1, Sp3, Sp4, IGF-1 receptor, EGFR, anticancer activity, chemoprevention, drug repurposing
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Male, Metformin, Mice, Nude, Pancreatic Neoplasms, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, ras Proteins, Cell Line, Tumor, Mice, Sp Transcription Factors, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
