Abstract
Hypoxia plays an important role in the resistance of tumour cells to chemotherapy. However, the exact mechanisms underlying this process are not well understood. Moreover, according to the cell lines, hypoxia differently influences cell death. The study of the effects of hypoxia on the apoptosis induced by 5 chemotherapeutic drugs in 7 cancer cell types showed that hypoxia generally inhibited the drug-induced apoptosis. In most cases, the effect of hypoxia was the same for all the drugs in one cell type. The expression profile of 93 genes involved in apoptosis as well as the protein level of BCL-2 family proteins were then investigated. In HepG2 cells that are strongly protected against cell death by hypoxia, hypoxia decreased the abundance of nearly all the pro-apoptotic BCL-2 family proteins while none of them are decreased in A549 cells that are not protected against cell death by hypoxia. In HepG2 cells, hypoxia decreased NOXA and BAD abundance and modified the electrophoretic mobility of BIMEL. BIM and NOXA are important mediators of etoposide-induced cell death in HepG2 cells and the hypoxia-induced modification of these proteins abundance or post-translational modifications partly account for chemoresistance. Finally, the modulation of the abundance and/or of the post-translational modifications of most proteins of the BCL-2 family by hypoxia involves p53-dependent and –independent pathways and is cell type-dependent. A better understanding of these cell-to-cell variations is crucial in order to overcome hypoxia-induced resistance and to ameliorate cancer therapy.
Highlights
Cancer is one of the main causes of death in developed countries
In order to obtain further insight of the mechanisms initiated by hypoxia that lead to cancer cell resistance, we extended our previous observations using other cancer cell lines originating from various organs and having different p53 status and other apoptosis-inducing chemotherapeutic drugs that target different cellular pathways
Recent studies have focused on molecular markers of hypoxia (HIF-1a or CAIX) that demonstrate the presence of hypoxic areas within the tumours and not within healthy tissues but these surrogate markers do not give absolute values
Summary
Cancer is one of the main causes of death in developed countries. Treatments often include the use of chemotherapies but drug resistance is a common cause of treatment failure and relapse. Apoptosis is regulated by proteins of the BCL-2 (B-cell lymphoma-2) family that mainly act at the mitochondrial level This family of proteins can be subdivided into three categories according to the function and structure of the proteins [1]. The BAX-like proteins, such as BAX (BCL-2 associated 6 protein) and BAK (BCL-2 homologous antagonist/ killer), are death factors. Once activated, they oligomerise at the mitochondria and induce mitochondrial outer membrane permeabilisation, which provokes cell death. The BCL-2-like proteins, such as BCL-2, BCL-xL (B-cell lymphoma-extra large), BCL-w and MCL-1 (myeloid cell leukaemia 1), are survival factors. They form heterodimers with BAX/BAK and inhibit their action. They become transcriptionally upregulated and/or post-translationally modified (and/or relocalised) to gain their full proapoptotic function [1,2]
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