ИСТИНА

A hypoxic environment of rapidly growing tumor cells makes them resistant to antitumor drugs. In various cells, hypoxia suppressed cell death induced by widely used anticancer drugs doxorubicin or cisplatin, assessed by size of SubG1 population, cytochrome c release from mitochondria, the processing of caspase-3 and cleavage of its substrate, PARP. One of the reasons for apoptosis suppression is downregulation of p53 expression under hypoxic conditions, and, as a result, attenuation of the expression of pro-apoptotic Bcl-2 family proteins. Indeed, p53 knock-out did not affect the stabilization of hypoxia-inducible factor but made undetectable the expression of several pro-apoptotic proteins. Targeting mitochondria is an important tool in tumor cell elimination. Thus, thenoyltrifluoroacetone (TTFA), an inhibitor of Complex II in the respiratory chain, stimulated cisplatin-induced apoptosis in various cell lines in normoxia but not in hypoxia. This can be explained by the elimination of mitochondria involved in triggering apoptosis by mitophagy, either Parkin-dependent or receptor-mediated. Treatment with TTFA did not cause accumulation of PINK1, meaning that under hypoxic conditions cells survive through activation of a receptor-mediated pathway. Hypoxia triggers the accumulation of BNIP3 and BNIP3L, key receptors of mitophagy. Surprisingly, a BNIP3 knockout did not abolish hypoxia-induced protection; however, a compensatory upregulation of BNIP3L was detected. Thus, in the absence of BNIP3, mitophagy could be maintained by BNIP3L. When both BNIP3 and BNIP3L were knocked out, the inhibitory effect of hypoxia on apoptosis was diminished, although not abolished completely. Undoubtedly, receptor-mediated mitophagy is likely to be one of the mechanisms responsible for cell death suppression under hypoxic conditions.