Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1.

Helena Doktorova,Tomas Eckschlager,Jan Hrabeta,Mohamed Ashraf Khalil

doi:10.5507/bp.2015.025

Helena Doktorova, Tomas Eckschlager + Show 2 more

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https://doi.org/10.5507/bp.2015.025

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Journal: Biomedical Papers	Publication Date: May 19, 2015
Citations: 92	License type: cc-by

Affiliation: Charles University

Abstract

The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use. Hypoxia is a common feature of tumors and represents an independent prognostic factor in many cancers. It is the result of imbalances in the intake and consumption of oxygen caused by abnormal vessels in the tumor and the rapid proliferation of cancer cells. Hypoxia-induced resistance to cisplatin, doxorubicin, etoposide, melphalan, 5-flouoruracil, gemcitabine, and docetaxel has been reported in a number of experiments. Adaptation of tumor cells to hypoxia has important biological effects. The most studied factor responsible for these effects is hypoxia-inducible factor-1 (HIF-1) that significantly contributes to the aggressiveness and chemoresistance of different tumors. The HIF-1 complex, induced by hypoxia, binds to target genes, thereby increasing the expression of many genes. In addition, the expression of hundreds of genes can be also decreased in response to hypoxia in HIF-1 dependent manner, but without the detection of HIF-1 in these genes' promoters. HIF-1 independent mechanisms for drug resistance in hypoxia have been described, however, they are still rarely reported. The first clinical studies focusing on diagnosis of hypoxia and on inhibition of hypoxia-induced changes in cancer cells are starting to yield results. The adaptation to hypoxia requires many genetic and biochemical responses that regulate one another. Hypoxia-induced resistance is a very complex field and we still know very little about it. Different approaches to circumvent hypoxia in tumors are under development.

Highlights

The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use
The details of regulation regulated by HIF-1α repress DAPK and KLF4 regulated by HIF-1α, can negatively influence the stability and activity of HIF-1α regulated by Akt[2] or RAS/ERK signaling, activate Akt and ERK1/2 pathways leading to the elevation of HIF-1α and Vascular endothelial growth factor (VEGF) stabilize HIF-1α, inhibit the expression of E2F3 and MNT, down-regulates VMP1 suppress CUL2 regulates HIF-1α regulated by wild-type p53, stabilize HIF-1α reduce the inhibition of HIF-1β regulated by HIF-1α stabilize HIF-1α
Hypoxia selects more resistant cells having aggressive and metastatic phenotypes, which are often associated with poor prognoses, e.g., prostate cancer cells

Summary

Background

The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use. The association of HIF-1α overexpression with cell proliferation and poor prognosis has been observed in many human cancers[35,36,55] Many of these HIF-1 inducible genes such as VEGF, Glut-1, MDR, and Bcl-2 directly or indirectly mediate chemoresistance[19].in a wide range of different tumor types, e.g. hepatocellular carcinoma, neuroblastoma, and lung cancer, inhibition of HIF-1α resensitizes cells to drug treatment in hypoxia and is a valid target to reverse hypoxia-induced drug resistance[8,9,15,19,21,25,27,28,29,30,56]. The details of regulation regulated by HIF-1α (via TWIST) repress DAPK and KLF4 (role in metastasis) regulated by HIF-1α, can negatively influence the stability and activity of HIF-1α regulated by Akt[2] (via NF-κB and CREB) or RAS/ERK signaling, activate Akt and ERK1/2 pathways leading to the elevation of HIF-1α and VEGF (via targeting PTEN) stabilize HIF-1α (via GPD1L repression), inhibit the expression of E2F3 and MNT (control cell cycle progression), down-regulates VMP1 suppress CUL2 (can stabilize HIF-1α) regulates HIF-1α (angiogenesis) regulated by wild-type p53, stabilize HIF-1α reduce the inhibition of HIF-1β (promotes angiogenesis) regulated by HIF-1α stabilize HIF-1α

HeLa cells HNSCC Neuroblastoma OSCC Prostate cancer

Resistance phenotype

FUTURE PERSPECTIVES

Findings

CONCLUSIONS