Targeting Tumor Adaption to Chronic Hypoxia: Implications for Drug Resistance, and How It Can Be Overcome

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2017 Aug 26

PMID 28841148

Citations 40

Authors

Jae-Young Kim

Joo-Yong Lee

Affiliations

Soon will be listed here.

Abstract

The rapid and uncontrolled proliferation of tumors limits the availability of oxygen and nutrients supplied from the tumor vasculature, thus exposing them to low oxygen environments. Thus, diminished oxygen availability, or hypoxia, is the most common microenvironment feature of nearly all solid tumors. All living cells have the ability to sense changes in oxygen tension and adapt to this stress to preserve survival. Likewise, cancer cells adapt to chronic hypoxic stress via several mechanisms, including promotion of angiogenic factor production, metabolic shift to consume less oxygen, and reduction of apoptotic potential. Adaptation of tumor cells to hypoxia is believed to be the main driver for selection of more invasive and therapy-resistant cancer phenotypes. In this review, we discuss molecular mechanisms by which tumor cells adapt to hypoxia, with a specific focus on hypoxia-inducible factor (HIF) transcription factor. We further discuss the current understandings on hypoxia-mediated drug resistance and strategies to overcome it.

Citing Articles

Hypoxia drives CBR4 down-regulation promotes gastroenteropancreatic neuroendocrine tumors via activation mammalian target of rapamycin mediated by fatty acid synthase.

Ye M, Xu L, Lu F, Chen L, Hu C, Chen J J Cell Commun Signal. 2024; 18(3):e12041.

PMID: 39524139 PMC: 11544642. DOI: 10.1002/ccs3.12041.

Cellular and Molecular Mechanisms of Chemoresistance for Gastric Cancer.

Li Z, Shu X, Liu X, Li Q, Hu Y, Jia B Int J Gen Med. 2024; 17:3779-3788.

PMID: 39224691 PMC: 11368108. DOI: 10.2147/IJGM.S473749.

Hypoxia-induced LAMB2-enriched extracellular vesicles promote peritoneal metastasis in gastric cancer via the ROCK1-CAV1-Rab11 axis.

Li D, Jin Y, He X, Deng J, Lu W, Yang Z Oncogene. 2024; 43(37):2768-2780.

PMID: 39138263 DOI: 10.1038/s41388-024-03124-y.

Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance.

Cunha A, Silva P, Sarmento B, Queiros O Pharmaceutics. 2023; 15(11).

PMID: 38004589 PMC: 10675572. DOI: 10.3390/pharmaceutics15112610.

N-Acetyl-L-Cysteine Reduces Cervical Carcinogenesis by Promoting Apoptosis.

Guo W, Jing W Drugs R D. 2023; 23(2):165-174.

PMID: 37266883 PMC: 10293158. DOI: 10.1007/s40268-023-00423-9.

References

Blum R, Jacob-Hirsch J, Amariglio N, Rechavi G, Kloog Y . Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death. Cancer Res. 2005; 65(3):999-1006. View

Cao Z, Fang J, Xia C, Shi X, Jiang B . trans-3,4,5'-Trihydroxystibene inhibits hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression in human ovarian cancer cells. Clin Cancer Res. 2004; 10(15):5253-63. DOI: 10.1158/1078-0432.CCR-03-0588. View

Sivridis E, Koukourakis M, Mendrinos S, Karpouzis A, Fiska A, Kouskoukis C . Beclin-1 and LC3A expression in cutaneous malignant melanomas: a biphasic survival pattern for beclin-1. Melanoma Res. 2011; 21(3):188-95. DOI: 10.1097/CMR.0b013e328346612c. View

Kong D, Park E, Stephen A, Calvani M, Cardellina J, Monks A . Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res. 2005; 65(19):9047-55. DOI: 10.1158/0008-5472.CAN-05-1235. View

Vaupel P . Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol. 2004; 14(3):198-206. DOI: 10.1016/j.semradonc.2004.04.008. View

Grahame Hardie D, Sakamoto K . AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda). 2006; 21:48-60. DOI: 10.1152/physiol.00044.2005. View

LaCasse E, Baird S, Korneluk R, Mackenzie A . The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene. 1999; 17(25):3247-59. DOI: 10.1038/sj.onc.1202569. View

Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S . BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol. 2000; 20(15):5454-68. PMC: 85997. DOI: 10.1128/MCB.20.15.5454-5468.2000. View

Jiang B, Agani F, Passaniti A, Semenza G . V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 1997; 57(23):5328-35. View

10.

Folkman J, Hahnfeldt P, Hlatky L . Cancer: looking outside the genome. Nat Rev Mol Cell Biol. 2001; 1(1):76-9. DOI: 10.1038/35036100. View

11.

Semenza G . Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol. 2013; 9:47-71. DOI: 10.1146/annurev-pathol-012513-104720. View

12.

Mizuno T, Nagao M, Yamada Y, Narikiyo M, Ueno M, Miyagishi M . Small interfering RNA expression vector targeting hypoxia-inducible factor 1 alpha inhibits tumor growth in hepatobiliary and pancreatic cancers. Cancer Gene Ther. 2005; 13(2):131-40. DOI: 10.1038/sj.cgt.7700871. View

13.

Konopleva M, Thall P, Arana Yi C, Borthakur G, Coveler A, Bueso-Ramos C . Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia. Haematologica. 2015; 100(7):927-34. PMC: 4486227. DOI: 10.3324/haematol.2014.118455. View

14.

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

15.

Puri N, Khramtsov A, Ahmed S, Nallasura V, Hetzel J, Jagadeeswaran R . A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. Cancer Res. 2007; 67(8):3529-34. DOI: 10.1158/0008-5472.CAN-06-4416. View

16.

Yang Z, Chee C, Huang S, Sinicrope F . The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011; 10(9):1533-41. PMC: 3170456. DOI: 10.1158/1535-7163.MCT-11-0047. View

17.

Boyd J, Malstrom S, Subramanian T, Venkatesh L, Schaeper U, Elangovan B . Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell. 1994; 79(2):341-51. DOI: 10.1016/0092-8674(94)90202-x. View

18.

Mabjeesh N, Post D, Willard M, Kaur B, Van Meir E, Simons J . Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells. Cancer Res. 2002; 62(9):2478-82. View

19.

Franovic A, Gunaratnam L, Smith K, Robert I, Patten D, Lee S . Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc Natl Acad Sci U S A. 2007; 104(32):13092-7. PMC: 1941796. DOI: 10.1073/pnas.0702387104. View

20.

Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio P . Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003; 3(4):347-61. DOI: 10.1016/s1535-6108(03)00085-0. View