Mechanism of HIF-1alpha-dependent Suppression of Hypoxia-induced Apoptosis in Squamous Cell Carcinoma Cells

Overview

Journal Cancer Sci

Specialty Oncology

Date 2005 Aug 2

PMID 16053510

Citations 57

Authors

Eri Sasabe

Yukihiro Tatemoto

Dechao Li

Tetsuya Yamamoto

Tokio Osaki

Affiliations

Soon will be listed here.

Abstract

The transcriptional factor hypoxia-inducible factor-1 (HIF-1) plays an important role in solid tumor cell growth and survival. Overexpression of HIF-1alpha has been demonstrated in many human tumors and predicts a poor response to chemoradiotherapy. We examined the HIF-1alpha-induced survival pathways in human oral squamous cell carcinoma cell (OSCC) lines. The results showed that forced expression of HIF-1alpha suppressed hypoxia-induced apoptosis of OSCC lines by inhibiting cytochrome c release from mitochondria. Overexpression of HIF-1alpha inhibited the generation of reactive oxygen species (ROS), elevation of intracellular Ca(2+) concentration, reduction of mitochondrial membrane potential, and cytosolic accumulation of cytochrome c, which resulted in the inactivation of caspase-9 and caspase-3. In addition, antiapoptotic Bcl-2 and Bcl-X(L) levels were increased and pro-apoptotic Bax and Bak levels were decreased in the HIF-1alpha-overexpressing OSCC line. Overexpression of HIF-1alpha also increased the levels of phosphorylation of Akt and extracellular signal-regulated kinases (ERK). These findings indicate that HIF-1alpha prevents apoptotic cell death through two mechanisms, including inhibition of cytochrome c release and activation of Akt and ERK.

Citing Articles

Targeting Mitochondrial Dysfunction in Cerebral Ischemia: Advances in Pharmacological Interventions.

Belenichev I, Popazova O, Bukhtiyarova N, Ryzhenko V, Pavlov S, Suprun E Antioxidants (Basel). 2025; 14(1).

PMID: 39857442 PMC: 11760872. DOI: 10.3390/antiox14010108.

Repurposing neuroleptics: clozapine as a novel, adjuvant therapy for melanoma brain metastases.

Wikerholmen T, Taule E, Rigg E, Berle B, Saettem M, Sarnow K Clin Exp Metastasis. 2025; 42(2):12.

PMID: 39856383 PMC: 11761981. DOI: 10.1007/s10585-025-10328-3.

Hypoxia-inducible factor in breast cancer: role and target for breast cancer treatment.

Zhi S, Chen C, Huang H, Zhang Z, Zeng F, Zhang S Front Immunol. 2024; 15:1370800.

PMID: 38799423 PMC: 11116789. DOI: 10.3389/fimmu.2024.1370800.

Neuroadaptive Biochemical Mechanisms of Remote Ischemic Conditioning.

Baranova K, Nalivaeva N, Rybnikova E Int J Mol Sci. 2023; 24(23).

PMID: 38069355 PMC: 10707673. DOI: 10.3390/ijms242317032.

High oxygen-modified packaging (HiOx-MAP) mediates HIF-1α regulation of tenderness changes during postmortem aging of yak meat.

Xin K, Tian K, Yu Q, Han L Food Chem X. 2023; 17:100573.

PMID: 36845525 PMC: 9945635. DOI: 10.1016/j.fochx.2023.100573.

References

Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu M . Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 2000; 60(6):1541-5. View

Semenza G . Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol. 1999; 59(1):47-53. DOI: 10.1016/s0006-2952(99)00292-0. View

SALCEDA S, Caro J . Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem. 1997; 272(36):22642-7. DOI: 10.1074/jbc.272.36.22642. View

Sowter H, Ratcliffe P, Watson P, Greenberg A, Harris A . HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 2001; 61(18):6669-73. View

Jiang B, Jiang G, Zheng J, Lu Z, Hunter T, Vogt P . Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ. 2001; 12(7):363-9. View

Huang L, Gu J, Schau M, BUNN H . Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A. 1998; 95(14):7987-92. PMC: 20916. DOI: 10.1073/pnas.95.14.7987. View

Cardone M, Roy N, Stennicke H, Salvesen G, Franke T, Stanbridge E . Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998; 282(5392):1318-21. DOI: 10.1126/science.282.5392.1318. View

Porter A, Vaillancourt R . Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis. Oncogene. 1998; 17(11 Reviews):1343-52. DOI: 10.1038/sj.onc.1202171. View

Alvarez-Tejado M, Alfranca A, Aragones J, Vara A, Landazuri M, Del Peso L . Lack of evidence for the involvement of the phosphoinositide 3-kinase/Akt pathway in the activation of hypoxia-inducible factors by low oxygen tension. J Biol Chem. 2002; 277(16):13508-17. DOI: 10.1074/jbc.M200017200. View

10.

Mottet D, Dumont V, Deccache Y, Demazy C, Ninane N, Raes M . Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells. J Biol Chem. 2003; 278(33):31277-85. DOI: 10.1074/jbc.M300763200. View

11.

Sharpe J, Arnoult D, Youle R . Control of mitochondrial permeability by Bcl-2 family members. Biochim Biophys Acta. 2004; 1644(2-3):107-13. DOI: 10.1016/j.bbamcr.2003.10.016. View

12.

Erler J, Cawthorne C, Williams K, Koritzinsky M, Wouters B, Wilson C . Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol Cell Biol. 2004; 24(7):2875-89. PMC: 371100. DOI: 10.1128/MCB.24.7.2875-2889.2004. View

13.

Maxwell P, Dachs G, Gleadle J, Nicholls L, Harris A, Stratford I . Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 1997; 94(15):8104-9. PMC: 21564. DOI: 10.1073/pnas.94.15.8104. View

14.

Festjens N, van Gurp M, van Loo G, Saelens X, Vandenabeele P . Bcl-2 family members as sentinels of cellular integrity and role of mitochondrial intermembrane space proteins in apoptotic cell death. Acta Haematol. 2003; 111(1-2):7-27. DOI: 10.1159/000074483. View

15.

Vaupel P, Kallinowski F, Okunieff P . Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989; 49(23):6449-65. View

16.

RYAN H, Poloni M, McNULTY W, Elson D, Gassmann M, Arbeit J . Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res. 2000; 60(15):4010-5. View

17.

Dachs G, Patterson A, Firth J, Ratcliffe P, Townsend K, Stratford I . Targeting gene expression to hypoxic tumor cells. Nat Med. 1997; 3(5):515-20. DOI: 10.1038/nm0597-515. View

18.

Zhong H, De Marzo A, Laughner E, Lim M, Hilton D, Zagzag D . Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999; 59(22):5830-5. View

19.

Wang G, Jiang B, Rue E, Semenza G . Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92(12):5510-4. PMC: 41725. DOI: 10.1073/pnas.92.12.5510. View

20.

Zhou H, Li X, Meinkoth J, Pittman R . Akt regulates cell survival and apoptosis at a postmitochondrial level. J Cell Biol. 2000; 151(3):483-94. PMC: 2185587. DOI: 10.1083/jcb.151.3.483. View