HIF-1 in cancer therapy: two decade long story of a transcription factor
Open accessAbstract
Background: Oxygen (O2) homeostasis is an indispensable requirement of eukaryotes. O2 concentration in cellular milieu is defined as normoxia (∼21% O2), physoxia (∼1–13% O2) or hypoxia (∼0.1–1% O2). Hypoxia, a striking micro-environmental feature in tumorigenesis, is countered by tumor cells via induction of O2 governed transcription factor, hypoxia inducible factor-1 (HIF-1). Post discovery, HIF-1 has emerged as a promising anticancer therapeutic target during the last two decades. Recent reports have highlighted that enhanced levels of HIF-1 correlate with tumor metastasis leading to poor patient prognosis.Material and methods: A systematic search in PubMed and SciFinder for the literature on HIF-1 biology and therapeutic importance in cancer was carried out.Results: This review highlights the initial description as well as the recent insights into HIF-1 biology and regulation. We have focused on emerging data regarding varied classes of HIF-1 target genes affecting various levels of crosstalk among tumorigenic pathways. We have emphasized on the fact that HIF-1 acts as a networking hub coordinating activities of multiple signaling molecules influencing tumorigenesis. Emerging evidences indicate role of many HIF-induced proteomic and genomic alterations in malignant progression by mediating a myriad of genes stimulating angiogenesis, anaerobic metabolism and survival of cancer cells in O2-deficient microenvironment.Conclusions: Better understanding of the crucial role of HIF-1 in carcinogenesis could offer promising new avenues to researchers and aid in elucidating various open issues regarding the use of HIF-1 as an anticancer therapeutic target. In spite of large efforts in this field, many questions still remain unanswered. Hence, future investigations are necessary to devise, assess and refine methods for translating previous research efforts into novel clinical practices in cancer treatment.
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No specific HIF inhibitor has been approved for clinical use.
“However, no specific HIF inhibitor has been approved for clinical use8.”
From Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer (2020) · cites this paper as [8]
HIF-1α drives tumor progression because it orchestrates angiogenesis, glycolytic switch, and metastasis.
“HIF-1α drives tumor progression because it orchestrates fundamental processes such as angiogenesis, glycolytic switch, and metastasis8.”
From Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer (2020) · cites this paper as [8]
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Recent agents targeting HIF‐1α for cancer therapy
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“Additionally, it has been reported that elevated nitric oxide (NO) levels and enhanced expression of nitric oxide synthase (NOS) isoforms increases HIF-1a protein stability in human oral squamous cell carcinoma [42] (Table 1).”
BackgroundHIF-1α can act as a tumor suppressor gene in murine acute myeloid leukemia
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Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD
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“Recent reports have exhibited that p53 is stimulated by hypoxia and acts as a negative regulator of glycolysis [74] (Figure 4).”
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Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells
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“Poly (ADP-ribose) polymerase 1 (PARP1) is one more NADþ-dependent enzyme, which was reported to interact with and promote HIF-1a transactivation [41].”
BackgroundShay, J. E. S., Imtiyaz, H. Z., Sivanand, S., Durham, A. C., Skuli, N., Hsu, S., Mucaj, V., Eisinger‐Mathason, T. S. K., Krock, B. L., Giannoukos, D. N., et al. (2014) · Carcinogenesis · doi:10.1093/carcin/bgu004 · Cited by 69 · see citing works
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“These nicotinamide adenine dinucleotide (NADþ)-dependent enzymes have exhibited potential to regulate HIF activity, thereby strengthening the association between HIF responses and cellular stress [40].”
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“Interestingly, HIF-1a induces glycolysis and actively restrains mitochondrial function and O2 utilization by inducing pyruvate dehydrogenase kinase-1 (PDK-1) activity [68].”
BackgroundKamat, C. D., Green, D. E., Warnke, L. A., Thorpe, J. E., Ceriello, A., & Ihnat, M. A. (2006) · Cancer Letters · doi:10.1016/j.canlet.2006.08.017 · Cited by 53 · see citing works
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“These include platelet-derived growth factor (PDGF) [37], insulin [38] and insulin-like growth factors (IGF) [39], which induces HIF-1a translation (Table 1).”
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Hypoxia inhibits mesenchymal stem cell proliferation through HIF1α-dependent regulation of P27
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“BCL2/ adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) is a HIF-1 target gene correlated to autophagy [72] through disruption of interaction between Beclin-1 (a highly conserved autophagy inducer protein) and B-cell lymphoma 2 (Bcl-2) or B-cell lymphoma-extra-large (Bcl-xL) [73].”
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Leu-574 of HIF-1α Is Essential for the von Hippel-Lindau (VHL)-mediated Degradation Pathway
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“Collectively, these alterations lead to 26S proteasomal degradation of HIF-1a subunit by tethering to the b-domain of von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase at Leucine-574 (L574) [18].”
BackgroundCarrera, S., Senra, J. M., Acosta, M. I., Althubiti, M., Hammond, E. M., de Verdier, P. J., & Macip, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097938 · Cited by 34 · cited 1× · see citing works
“Recently HIF-1a has been reported to be activated at physiological O2 levels in a p42/44 mitogen-activated protein kinase (MAPK)dependent manner determining increased cellular proliferation commonly found in these conditions [36].”
BackgroundGreco, S., & Martelli, F. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6083 · Cited by 34 · cited 1× · see citing works
“Previous studies have demonstrated number of miRNAs induced during hypoxia and they play critical roles in angiogenesis [80].”
BackgroundYoo, B. H., Wu, X., Derouet, M. F., Haniff, M., Eskelinen, E., & Rosen, K. V. (2009) · Autophagy · doi:10.4161/auto.5.8.10167 · Cited by 32 · see citing works
Curcumin induces p53-independent necrosis in H1299 cells via a mitochondria-associated pathway
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“These include platelet-derived growth factor (PDGF) [37], insulin [38] and insulin-like growth factors (IGF) [39], which induces HIF-1a translation (Table 1).”
BackgroundAntagonistic crosstalk between APC and HIF-1α
Näthke, I. S., & Rocha, S. (2011) · Cell Cycle · doi:10.4161/cc.10.10.15638 · Cited by 19 · see citing works
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“BCL2/ adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) is a HIF-1 target gene correlated to autophagy [72] through disruption of interaction between Beclin-1 (a highly conserved autophagy inducer protein) and B-cell lymphoma 2 (Bcl-2) or B-cell lymphoma-extra-large (Bcl-xL) [73].”
BackgroundMuh, C. R., Joshi, S., Singh, A. R., Kesari, S., Durden, D. L., & Makale, M. (2013) · Journal of Neuro-Oncology · doi:10.1007/s11060-013-1283-3 · Cited by 16 · see citing works
Expression of Hypoxia Inducible Factor-1α and Its Significance in Laryngeal Carcinoma
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“Very little was known about the newest isoform HIF-3a until the identification of its spliced variant, inhibitory PAS (IPAS) which in a dominant negative way regulates HIF-1 DNA binding ability [29].”
BackgroundHIF1A expression in localized prostate cancer treated with dose escalation radiation therapy
Zapatero, A., Morente, M. M., de Vidales, C. M., Adrados, M., López, C., Nieto, S., González, M. J. A., Arellano, R., Conde, A. C., & Vicente, F. G. (2015) · Cancer Biomarkers · doi:10.3233/cbm-140439 · Cited by 7 · see citing works
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“HRE, they are functionally non-redundant [26].”
Hypoxia-Inducible Factor 1A in Clear Cell Renal Cell Carcinoma
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“Since the discovery of HIFs, many inhibitors with diverse modes of action have been identified, but none have progressed to clinical use [119].”
BackgroundThe anti-cancer effect of quercetin: molecular implications in cancer metabolism
Reyes-Farias, M., & Carrasco-Pozo, C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133177 · Cited by 689 · see citing works
“In fact, HIF-1α is the primary driver of increased glycolysis and lactate production during hypoxia [35].”
BackgroundThe Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents
Zhou, J., Kang, Y., Chen, L., Wang, H., Liu, J., Zeng, S., & Yu, L. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00343 · Cited by 481 · see citing works
“Whereas under hypoxic conditions, impaired hydroxylation process stabilizes the HIF1a protein, furthermore HIF1a will translocate into nuclear and dimerize with HIF1b to transactivate the target genes which relate with glucose metabolism, angiogenesis, cell proliferation, invasion and metastasis (reviewed in Pawlus an…”
BackgroundMarra, A., Trapani, D., Viale, G., Criscitiello, C., & Curigliano, G. (2020) · npj Breast Cancer · doi:10.1038/s41523-020-00197-2 · Cited by 316 · see citing works
HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies
Zhao, Y., Xing, C., Deng, Y., Ye, C., & Peng, H. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.02.039 · Cited by 214 · see citing works
“It has been reported that HIF-1a is highly expressed in tumors such as breast, liver, bladder, cervical, colorectal, endometrial, lung, etc.(77) NANOG is a protein required for the self-renewal of breast cancer stem cells (BCSCs), and high expression of NANOG in tumor tissues of breast cancer patients is correlated wi…”
BackgroundHonokiol: A Review of Its Anticancer Potential and Mechanisms
Ong, C. P., Lee, W. L., Tang, Y.-Q., & Yap, W. H. (2019) · Cancers · doi:10.3390/cancers12010048 · Cited by 201 · see citing works
“An activation of the HIF pathway leading to hypoxia-induced neovascularisation is the central cause of pathogenesis in almost all solid tumours and ischemic retinal diseases [198,199].”
BackgroundHypoxia and Selective Autophagy in Cancer Development and Therapy
Daskalaki, I., Gkikas, I., & Tavernarakis, N. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00104 · Cited by 188 · see citing works
“For example, BNIP3 and NIX are highly expressed in breast, macrophage, endothelial and epithelial cancer cells compared to healthy cells from the same patient upon hypoxia induction (Sowter et al., 2001).”
BackgroundFunctions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway
Sondermann, N. C., Faßbender, S., Hartung, F., Hätälä, A. M., Rolfes, K. M., Vogel, C. F. A., & Haarmann‐Stemmann, T. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115371 · Cited by 190 · see citing works
Hypoxia-induced epithelial to mesenchymal transition in cancer
Hapke, R., & Haake, S. M. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.05.012 · Cited by 181 · see citing works
“However, the role of HIFs in cancer development extends beyond angiogenesis, and includes reprograming metabolism, regulating cell proliferation and survival, and increasing therapeutic resistance[17].”
BackgroundLiu, Z., Wang, Y., Dou, C., Xu, M. M., Sun, L., Wang, L., Yao, B., Li, Q., Yang, W., Tu, K., et al. (2018) · Theranostics · doi:10.7150/thno.26789 · Cited by 172 · see citing works
“HIF-1α is highly expressed and significantly associated with advanced stage and aggressive phenotype in HCC and is indicative of poor prognosis [9, 10].”
BackgroundBui, B. P., Nguyen, P. L., Lee, K., & Cho, J. (2022) · Cancers · doi:10.3390/cancers14246054 · Cited by 164 · see citing works
“promoting tumor cell growth, vascularization, and metastasis [7].”
BackgroundKabakov, A. E., & Yakimova, A. O. (2021) · Cancers · doi:10.3390/cancers13051102 · Cited by 161 · see citing works
“In contrast to the Snitrosation of HIF-1α at cysteine 800 that takes place under hypoxia and is required for HIF-1-mediated transcription (reviewed in [16]), the S-nitrosation of HIF-1α at cysteine 533 can occur in normoxic tumors undergoing radiation exposure [105].”
BackgroundHIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart
Čerychová, R., & Pavlínková, G. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00460 · Cited by 142 · see citing works
“Systemic administration of small-molecule inhibitors of HIF-1 activity with anticancer effects that impairs both vascular and metabolic adaptations have been successfully used in a number of preclinical studies (138).”
BackgroundEnolase 1, a Moonlighting Protein, as a Potential Target for Cancer Treatment
Qiao, G., Wu, A., Chen, X., Tian, Y., & Lin, X. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.63556 · Cited by 139 · see citing works
“In the cancer metabolic reprogramming, ENO1 stimulates cancer cells to create energy largely by disintegration of glucose in a non-oxidative manner rather than typical oxidative phosphorylation (17,18).”
BackgroundMa, Z., Xiang, X., Li, S., Xie, P., Gong, Q., Goh, B.-C., & Wang, L. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.09.011 · Cited by 135 · see citing works
Characteristics of the cancer stem cell niche and therapeutic strategies
Ju, F., Atyah, M. M., Horstmann, N., Gul, S., Vago, R., Bruns, C. J., Zhao, Y., Dong, Q., & Ren, N. (2022) · Stem Cell Research & Therapy · doi:10.1186/s13287-022-02904-1 · Cited by 129 · see citing works
“Furthermore, other agents, such as wortmannin, temsirolimus and camptothecin, have been proved to inhibit HIF-1α protein translation by targeting corresponding genes [138].”
BackgroundDou, C., Zhou, Z., Xu, Q., Liu, Z., Zeng, Y., Wang, Y., Li, Q., Wang, L., Yang, W., Liu, Q., et al. (2018) · Oncogene · doi:10.1038/s41388-018-0505-8 · Cited by 116 · see citing works
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“HIF-1α promotes tumor progression by regulating glycolysis, angiogenesis, and cell cycle progression of tumor cells [26, 27].”
BackgroundChen, Z., Hu, Z., Sui, Q., Huang, Y., Zhao, M., Li, M., Liang, J., Lu, T., Zhan, C., Lin, Z., et al. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.67556 · Cited by 112 · see citing works
“proliferation/viability, which has a crucial role in tumor survival and progression, leading to the increased possibility of metastasis as well as mortality rates clinically[58].”
BackgroundGabryelska, A., Karuga, F. F., Szmyd, B. M., & Białasiewicz, P. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.01035 · Cited by 106 · see citing works
“Further studies allowed for new glycolytic enzymes influenced by HIF-1α to be determined, namely, hexokinase 1, hexokinase 2 (Soni and Padwad, 2017), enolase 1, aldolase A, and phosphofructokinase L (Iyer et al.”
BackgroundHou, P., Shi, P.-C., Jiang, T., Yin, H., Chu, S., Shi, M., Bai, J., & Song, J. H. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0695-z · Cited by 98 · see citing works
“Under hypoxic conditions, HIF-1α accumulates in the cytosol and is translocated to the nucleus, thereby forming active HIF-1α with HIF-1β and regulating downstream target genes transcriptionally.(21) In this study, DKC1 can positively regulate HIF1α in hypoxic and normoxic environments (Fig.”
BackgroundNanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment
Pan, Y., Liu, L., Mou, X., & Cai, Y. (2023) · ACS Nano · doi:10.1021/acsnano.3c07763 · Cited by 98 · see citing works
Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment
Kim, I., Choi, S., Yoo, S., Lee, M., & Kim, I. (2022) · Cancers · doi:10.3390/cancers14143321 · Cited by 98 · see citing works
Su, Q., Fan, M., Wang, J., Ullah, A., Ghauri, M. A., Dai, B., Zhan, Y., Zhang, D., & Zhang, Y. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2173-1 · Cited by 92 · see citing works
Molecular Crosstalk Between MYC and HIF in Cancer
Li, Y., Sun, X., Qian, D. Z., & Dai, M. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.590576 · Cited by 90 · see citing works
“Most of the reported HIF1 inhibitors were originally used for targeting other endogenous proteins and later they were found to inhibit HIF1 activity (Masoud and Li, 2015; Wigerup et al., 2016; Soni and Padwad, 2017).”
BackgroundInfluentialBNIP3 promotes HIF‐1α‐driven melanoma growth by curbing intracellular iron homeostasis
Vara‐Pérez, M., Rossi, M., den Haute, C. V., Maes, H., Sassano, M. L., Venkataramani, V., Michalke, B., Romano, E., Rillaerts, K., Garg, A. D., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020106214 · Cited by 89 · see citing works
“…including: (i) Glut1, Hk2, Pdk1, Pkm2, and Ldha are well-established HIF-1 α targets and HIF-1 α is a master regulator of the Warburg effect in melanoma (Soni & Padwad, 2017; Lee et al, 2020); (ii) melanoma cells harbor constitutively high levels of HIF-1 α (Kuphal et al, 2010; Mart (cid:1) ı…”
Kao, T.-W., Bai, G.-H., Wang, T.-L., Shih, I.-M., Chuang, C.-M., Lo, C.-L., Tsai, M.-C., Chiu, L.-Y., Lin, C.-C., & Shen, Y.-A. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02724-y · Cited by 89 · see citing works
“G HNSCC Squamous cell carcinoma of the head and neck HRE Hypoxia responsive element Hsp90 Heat shock protein‑90 ICB Immune checkpoint blockade IL‑1β Interleukin‑1β MDR1 Multidrug resistant protein 1 MDSC Myeloid‑derived suppressor cells MHC Major histocompatibility complex MMP Matrix metalloproteinase MTD Maximum tole…”
BackgroundInfluentialHypoxia and HIF-1α Regulate Collagen Production in Keloids
Kang, Y., Roh, M. R., Rajadurai, S., Rajadurai, A., Kumar, R., Njauw, C.-N. J., Zheng, Z., & Tsao, H. (2020) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2020.01.036 · Cited by 86 · see citing works
Role of hypoxia inducible factor-1 in cancer stem cells (Review)
Zhang, Q., Han, Z., Zhu, Y., Chen, J., & Li, W. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11655 · Cited by 86 · see citing works
“HIF‐1β is stably expressed in cells and maintains the stability of HIF‐1 (21,22).”
BackgroundTranscriptional Regulation of Energy Metabolism in Cancer Cells
Rodríguez‐Enríquez, S., Marín‐Hernández, Á., Gallardo‐Pérez, J. C., Pacheco-Velázquez, S. C., Belmont-Díaz, J., Robledo‐Cadena, D. X., Vargas-Navarro, J. L., de la Peña, N. A. C., Saavedra, E., & Moreno‐Sánchez, R. (2019) · Cells · doi:10.3390/cells8101225 · Cited by 86 · see citing works
“HIF-1α Nuclei Angiogenesis, erythropoiesis, cellular proliferation, survival, vascular remodeling, tumorigenesis, invasion, metastasis [16]”
Ribeiro, R., Carvalho, M. J., Gonçalves, J., & Moreira, J. N. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.903065 · Cited by 84 · see citing works
“In spite of the search for molecular targets involved in hypoxia to overcome chemoresistance, no clinical benefit has been reported so far in this context (Soni and Padwad, 2017).”
BackgroundModulation of the tumor microenvironment (TME) by melatonin
Qi, M., & Najafi, M. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174365 · Cited by 82 · see citing works
Cancer stem cells and hypoxia-inducible factors (Review)
Tong, W., Tong, G., & Liu, Y. (2018) · International Journal of Oncology · doi:10.3892/ijo.2018.4417 · Cited by 78 · see citing works
“Virchow first proposed that some tumors may arise from embryo-like cells and that cancer cells have properties reminiscent of stem cells reported in 1855 (1).”
Hypoxia-Inducible Factors as an Alternative Source of Treatment Strategy for Cancer
Akanji, M. A., Rotimi, D. E., & Adeyemı, O. S. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/8547846 · Cited by 77 · see citing works
“HIF-1 stimulates genetic transcription such as proteases that degrade cathepsin C (CTSC), matrix metalloproteinase 2, 9, and 14, and the urokinase plasminogen activator receptor or remodel lysyl oxidase (LOX); the extracellular matrices within are of metastasis [5]”
BackgroundInfluentialTargeting glycolysis in non-small cell lung cancer: Promises and challenges
Xu, J.-Q., Fu, Y.-L., Zhang, J., Zhang, K.-Y., Ma, J., Tang, J.-Y., Zhang, Z.-W., & Zhou, Z.-Y. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1037341 · Cited by 75 · see citing works
“Most of the key glycolytic enzymes are affected by MYC and HIF-1α in tumor glycolysis metabolism (Stine et al., 2015; Soni and Padwad, 2017).”
BackgroundMutant p53 and Cellular Stress Pathways: A Criminal Alliance That Promotes Cancer Progression
D’Orazi, G., & Cirone, M. (2019) · Cancers · doi:10.3390/cancers11050614 · Cited by 68 · see citing works
“HIF-1 is considered the main effector of the cellular response to hypoxia inducing the transcription of target genes involved in many aspects of cancer progression, including angiogenesis, metabolic adaptation, chemoresistance, apoptosis evasion, invasion and metastasis, therefore, its targeting is considered a useful…”
BackgroundHIF-1α Metabolic Pathways in Human Cancer
Elzakra, N., & Kim, Y. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-51652-9_17 · Cited by 67 · see citing works
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Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences
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Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy
Kozal, K., Jóźwiak, P., & Krześlak, A. (2021) · Cancer Control · doi:10.1177/10732748211041243 · Cited by 63 · see citing works
“HIF-1 targets genes coding key elements of glucose metabolism such as glucose transporters, hexokinases, phosphofructokinase, or lactate dehydrogenase.(61) Because of the complexity of HIF-1 involvement in various pathways and mechanisms, targeting it as a potential anti-cancer therapy element suggests it is an option…”
BackgroundAnti-Cancer Immunotherapies Targeting Telomerase
Negrini, S. M., Palma, R. D., & Filaci, G. (2020) · Cancers · doi:10.3390/cancers12082260 · Cited by 62 · see citing works
Zhang, L., Ke, J., Min, S., Wu, N., Liu, F., Qu, Z., Li, W., Wang, H., Qian, Z., & Wang, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.691762 · Cited by 60 · see citing works
Hong, M., Shi, H., Wang, N., Tan, H., Wang, Q., & Feng, Y. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00696 · Cited by 59 · see citing works
Renfrow, J. J., Soike, M. H., West, J. L., Ramkissoon, S. H., Metheny-Barlow, L., Mott, R. T., Kittel, C. A., D’Agostino, R. B., Tatter, S. B., Laxton, A. W., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-72290-2 · Cited by 45 · see citing works
NOX as a Therapeutic Target in Liver Disease
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The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy
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Endometriosis and Cancer: Exploring the Role of Macrophages
Artemova, D. A., Vishnyakova, P., Khashchenko, K. E. P., Elchaninov, A. V., Sukhikh, G. T., & Fatkhudinov, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105196 · Cited by 53 · see citing works
Locatelli, F., Minutolo, R., Nicola, L. D., & Vecchio, L. D. (2022) · Drugs · doi:10.1007/s40265-022-01783-3 · Cited by 53 · see citing works
“A large body of evidence has shown increased expression of HIF-1α and HIF-2α inside tumour masses [141, 142].”
BackgroundNADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation
Szántó, I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052702 · Cited by 49 · see citing works
Targeting Tyrosine kinases in Renal Cell Carcinoma: “New Bullets against Old Guys”
Alonso‐Gordoa, T., García‐Bermejo, L., Grande, E., Garrido, P., Carrato, A., & Molina‐Cerrillo, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081901 · Cited by 49 · see citing works
“requires the presence of O2 and Fe+2 as co-factors and allows the binding of the VHL active complex to HIF α through its β domain, its ubiquitination and subsequent proteasome degradation [17,18].”
BackgroundPharmacological features, health benefits and clinical implications of honokiol
Khatoon, F., Ali, S., Kumar, V., Elasbali, A. M., Alhassan, H. H., Alharethi, S. H., Islam, A., & Hassan, M. I. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2022.2120541 · Cited by 50 · see citing works
“Hypoxia-induced neovascularisation led by HIF activation is the primary cause of the pathogenesis in all solid tumor and ischemic retinal diseases (Semenza, 2003; Soni & Padwad, 2017).”
González-Ruiz, R., Leyva‐Carrillo, L., Peregrino-Uriarte, A. B., & Yepiz-Plascencia, G. M. (2022) · Cell Stress and Chaperones · doi:10.1007/s12192-022-01265-1 · Cited by 46 · see citing works
Role of HIF-1α in the Responses of Tumors to Radiotherapy and Chemotherapy
Song, C. W., Kim, H., Kim, M.-S., Park, H. J., Paek, S.-H., Terezakis, S. A., & Cho, L. C. (2024) · Cancer Research and Treatment · doi:10.4143/crt.2024.255 · Cited by 55 · see citing works
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Kim, I., & Park, J. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.05.025 · Cited by 48 · see citing works
Transferrin receptor-involved HIF-1 signaling pathway in cervical cancer
Xu, X., Liu, T., Wu, J., Wang, Y., Hong, Y., & Zhou, H. (2019) · Cancer Gene Therapy · doi:10.1038/s41417-019-0078-x · Cited by 49 · see citing works
Hypoxia and its therapeutic possibilities in paediatric cancers
Bernauer, C., Man, Y. K. S., Chisholm, J., Lepicard, E. Y., Robinson, S. P., & SHIPLEY, J. M. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-01107-w · Cited by 48 · see citing works
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Sweet Cherries as Anti-Cancer Agents: From Bioactive Compounds to Function
Fonseca, L. R. S., Silva, G., Luís, Â., Cardoso, H. J., Correia, S., Vaz, C. V., Duarte, A. P., & Socorro, S. (2021) · Molecules · doi:10.3390/molecules26102941 · Cited by 45 · see citing works
“Moreover, in rat-induced esophageal tumors [102], anthocyanins from black raspberries decreased the levels of VEGF and hypoxia inducible factor-1, the main transcription factor governing the expression of genes and proteins implicated in the angiogenic process [103].”
BackgroundRedox regulation of cancer stem cells: Biology and therapeutic implications
Du, M., Zhang, J., Wicha, M. S., & Luo, M. (2024) · MedComm – Oncology · doi:10.1002/mog2.70005 · Cited by 45 · see citing works
Viswanath, P., Radoul, M., Izquierdo-García, J. L., Luchman, H. A., Cairncross, J. G., Pieper, R. O., Phillips, J. J., & Ronen, S. M. (2018) · Cancer & Metabolism · doi:10.1186/s40170-018-0178-3 · Cited by 46 · see citing works
“Under normoxic conditions, HIF-1α is targeted for proteasomal degradation as a result of prolyl hydroxylation that is mediated by α-KGdependent prolyl hydroxylases [45, 46].”
BackgroundSingh, S. K., Mishra, M. K., & Singh, R. (2019) · Journal of Ovarian Research · doi:10.1186/s13048-019-0517-1 · Cited by 45 · see citing works
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“HIF1A is a well-known factor involved in the adaptive metabolic response to hypoxia [28].”
BackgroundMorris, D. R., Qu, Y., Agrawal, A. S., Garofalo, R. P., & Casola, A. (2020) · Viruses · doi:10.3390/v12101088 · Cited by 45 · see citing works
“The activity of HIFs as a master regulator of cellular metabolism has been well characterized in a variety of cancer models [30].”
BackgroundRole of Glucose Metabolism Reprogramming in the Pathogenesis of Cholangiocarcinoma
Pant, K., Richard, S., Peixoto, E., & Gradilone, S. A. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00113 · Cited by 43 · see citing works
“During hypoxia, prolyl hydroxylation of HIF is withdrawn, resulting in stability and transcriptional activity of the HIF-1 protein complex (35, 36).”
BackgroundBolland, H. R., Ma, T. S., Ramlee, S., Ramadan, K., & Hammond, E. M. (2021) · Biochemical Society Transactions · doi:10.1042/bst20200861 · Cited by 42 · see citing works
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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
Hypoxia-induced cancer cell reprogramming: a review on how cancer stem cells arise
Abd, G. M., Laird, M. C., Ku, J. C., & Li, Y. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1227884 · Cited by 41 · see citing works
Targeting Stat3 signaling impairs the progression of bladder cancer in a mouse model.
Korac-Prlic, J., Degoricija, M., Vilović, K., Haupt, B., Ivanišević, T., Franković, L., Grivennikov, S., & Terzic, J. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.06.018 · Cited by 36 · see citing works
Functional Analysis of O-GlcNAcylation in Cancer Metastasis
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Fischer, F., Grigolon, G., Benner, C., & Ristow, M. (2022) · Physiological Reviews · doi:10.1152/physrev.00017.2021 · Cited by 41 · see citing works
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Angiogenesis and Hepatocellular Carcinoma: From Molecular Mechanisms to Systemic Therapies
Pinto, E., Pelizzaro, F., Farinati, F., & Russo, F. P. (2023) · Medicina · doi:10.3390/medicina59061115 · Cited by 41 · see citing works
“It triggers tumor cells invasion, acting in the epithelial–mesenchymal transition (EMT) process, increases cells proliferation and decreases apoptosis [42].”
BackgroundTargeting HIF-2α as therapy for advanced cancers
Murugesan, T., Rajajeyabalachandran, G., Kumar, S., Nagaraju, S., & Jegatheesan, S. K. (2018) · Drug Discovery Today · doi:10.1016/j.drudis.2018.05.003 · Cited by 39 · see citing works
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Strowd, R. E., III, Ellingson, B. M., Raymond, C., Yao, J., Wen, P. Y., Ahluwalia, M. S., Piotrowski, A. F., Desai, A. S., Clarke, J. L., Lieberman, F. S., et al. (2023) · Journal of Neuro-Oncology · doi:10.1007/s11060-023-04456-7 · Cited by 40 · see citing works
“HIF1α is ubiquitously expressed in both tumor and normal tissue limiting its therapeutic specificity [31, 32].”
BackgroundHenríquez, 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
Kozal, K., & Krześlak, A. (2022) · Cancers · doi:10.3390/cancers14184518 · Cited by 36 · see citing works
“For example, the M2 isoform of the pyruvate kinase, which is under the regulation of the hypoxia-inducible factor, enables redirecting glycolytic intermediates to other metabolic pathways and stimulates the increased transcriptional activity of the HIF factor by binding to the transactivation domain [42].”
BackgroundTherapeutic strategies for liver diseases based on redox control systems
Lee, J., Kim, J., Lee, R., Lee, E., Choi, T. G., Lee, A. S., Yoon, Y., Park, G., Namgoong, J., Lee, S., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113764 · Cited by 35 · see citing works
Oxidative stress as candidate therapeutic target to overcome microenvironmental protection of CLL
Yosifov, D. Y., Idler, I. S., Bhattacharya, N., Reichenzeller, M., Close, V., Ezeriņa, D., Scheffold, A., Jebaraj, B. M. C., Kugler, S. J., Bloehdorn, J., et al. (2019) · Leukemia · doi:10.1038/s41375-019-0513-x · Cited by 35 · see citing works
Mitochondria: A Galaxy in the Hematopoietic and Leukemic Stem Cell Universe
Panuzzo, C., Jovanovski, A., Pergolizzi, B., Pironi, L., Stanga, S., Fava, C., & Cilloni, D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113928 · Cited by 34 · see citing works
“Subsequently, HIF1a interacts with a constitutively expressed HIF1b subunit to form a complex able to coordinate the transcription of genes involved in the glycolytic process [98].”
BackgroundRamundo, V., Giribaldi, G., & Aldieri, E. (2021) · Cancers · doi:10.3390/cancers13123093 · Cited by 36 · see citing works
“Therefore, targeting specific mediators in these regulatory pathways may serve as novel therapeutic approaches for cancer treatment [51].”
BackgroundShaikat, A. H., Azad, S. M. A. K., Tamim, M. A. R., Ullah, M. S., Amin, M. N., Sabbir, M. K., Tarun, M. T. I., Mostaq, M. S., Sabrin, S., Mahmud, M. Z., et al. (2025) · Cancer Pathogenesis and Therapy · doi:10.1016/j.cpt.2025.07.003 · Cited by 36 · see citing works
“42 The interaction of these molecules with their particular receptors, such as the epidermal growth factor receptor ( EGFR ) and the insulin-like growth factor 1 receptor, starts signal transduction pathways that result in the synthesis of HIF-1 α and either supports cell survival or proliferation.”
Involvement of E3 Ligases and Deubiquitinases in the Control of HIF-α Subunit Abundance
Kubaichuk, K. I., & Kietzmann, T. (2019) · Cells · doi:10.3390/cells8060598 · Cited by 33 · see citing works
“HIF-1α is known to regulate the expression of more than 300 genes and noncoding RNAs [6,40], which control genomic stability, drug resistance, angiogenesis, vascular tone, glucose metabolism, cell proliferation, and survival.”
BackgroundSeo, J., Kim, K.-S., Park, J., Cho, J., Chang, H., Fukuda, J., Hong, K. Y., & Chun, Y. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120622 · Cited by 33 · see citing works
Transcriptional regulation of FoxM1 by HIF‑1α mediates hypoxia‑induced EMT in prostate cancer
Tang, C., Liu, T., Wang, K., Wang, X., Xu, S., He, D., & Zeng, J. (2019) · Oncology Reports · doi:10.3892/or.2019.7248 · Cited by 32 · see citing works
“These genes are regulated by the activation of the transcription factor HIF-1α, which serves an important role for the HIF family (41,42).”
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Metabolic Modifications by Common Respiratory Viruses and Their Potential as New Antiviral Targets
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“[20] observed that via the stabilization of HIF-1, an important metabolic regulator [37], RSV shifts the cell metabolism primarily from very oxygen-demanding pathways towards glycolysis and the PPP.”
BackgroundHIPK2 role in the tumor–host interaction: Impact on fibroblasts transdifferentiation CAF‐like
Garufi, A., Traversi, G., Cirone, M., & D’Orazi, G. (2019) · IUBMB Life · doi:10.1002/iub.2144 · Cited by 31 · see citing works
“HIPK2 corepresses hypoxia inducible factor 1α (HIF-1α),(10) a major player in cancer progression through transactivation of HIF-1 target genes involved in angiogenesis, glucose metabolism, chemotherapeutic resistance and invasion.(11) On the other hand, HIPK2 depletion activates β4 integrin transcription and the Akt p…”
BackgroundKim, J. Y., Cho, H., Yoo, J. H., Kim, G. W., Jeon, Y. H., Lee, S. W., & Kwon, S. H. (2023) · Cancers · doi:10.3390/cancers15041123 · Cited by 30 · see citing works
“Maintaining oxygen homeostasis is crucial for cell survival [6].”
BackgroundJalouli, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26041752 · Cited by 30 · see citing works
“The redundancy and overlap in the functions of these isoforms may impede the formulation of targeted therapeutic strategies for modulating autophagy in cancer cells [127].”
Fakhri, S., Moradi, S. Z., Faraji, F., Kooshki, L., Webber, K. J., & Bishayee, A. (2023) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10136-9 · Cited by 30 · see citing works
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“VEGF-A (a potent endothelial mitogen) is by far the most prominent protein among all these pro-angiogenic factors stimulated by HIF as it is highly expressed in several human tumors (216–218).”
Potential Roles of Hypoxia-Inducible Factor-1 in Alzheimer’s Disease: Beneficial or Detrimental?
Lin, T., Huang, C.-R., Lin, K.-J., Hsieh, Y.-H., Chen, S., Lin, Y., Chao, A., & Yang, D. (2024) · Antioxidants · doi:10.3390/antiox13111378 · Cited by 28 · see citing works
“…to accommodate the hypoxic conditions and serve as a network hub to coordinate relevant signaling molecules for the promotion of tumorigenesis [24,43] . in human cancers can modify cellular metabolisms; these include from oxidative phosphorylation to glycolysis, the enhanced synthesis of In…”
Molecular Functions of WWOX Potentially Involved in Cancer Development
Taouis, K., Driouch, K., Lidereau, R., & Lallemand, F. (2021) · Cells · doi:10.3390/cells10051051 · Cited by 28 · see citing works
“HIF1α, overexpressed in common human cancers, is essential to this cellular adaptation [96].”
Background
- Authors
- Soni, S., & Padwad, Y. S.
- Affiliations
- Institute of Himalayan Bioresource Technology (IN)
- Corresponding author
- Padwad, Yogendra S.
- Venue
- Acta Oncologica
- Published
- 2017-03-30
- Volume
- 56
- Issue
- 4
- Pages
- 503-515
- ISSN
- 0284-186X (ISSN-L)
- 1651-226X
- OpenAlex
- W2599085091
- Cited by
- 251
- References
- 122
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 16 · 2023: 35 · 2022: 34 · 2021: 38 · 2020: 41 · 2019: 43 · 2018: 20 · 2017: 1
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Acta Oncologica (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Council of Scientific and Industrial Research
- Council for Scientific and Industrial Research (MLP0039)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- HIF-1, tumor hypoxia, oxygen homeostasis, transcription factor regulation, HIF-1 target genes, tumor angiogenesis, anaerobic metabolism, metastasis, carcinogenesis, cancer therapy targets, tumor microenvironment
- MeSH terms
- Animals, Humans, Neoplasms, Cell Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit
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