Hypoxia-Induced Autophagy Promotes Tumor Cell Survival and Adaptation to Antiangiogenic Treatment in Glioblastoma

Abstract

Anti-angiogenic therapy leads to devascularization that limits tumor growth. However, the benefits of angiogenesis inhibitors are typically transient and resistance often develops. In this study, we explored the hypothesis that hypoxia caused by anti-angiogenic therapy induces tumor cell autophagy as a cytoprotective adaptive response, thereby promoting treatment resistance. Hypoxia-induced autophagy was dependent on signaling through the HIF-1α/AMPK pathway, and treatment of hypoxic cells with autophagy inhibitors caused a shift from autophagic to apoptotic cell death in vitro. In glioblastomas clinically resistant to the VEGF neutralizing antibody bevacizumab, increased regions of hypoxia and higher levels of autophagy-mediating BNIP3 were found when compared to pre-treatment specimens from the same patients. When treated with bevacizumab alone, human glioblastoma xenografts showed increased BNIP3 expression and hypoxia-associated growth, which could be prevented by addition of the autophagy inhibitor chloroquine. In vivo targeting of the essential autophagy gene ATG7 also disrupted tumor growth when combined with bevacizumab treatment. Together, our findings elucidate a novel mechanism of resistance to anti-angiogenic therapy in which hypoxia-mediated autophagy promotes tumor cell survival. One strong implication of our findings is that autophagy inhibitors may help prevent resistance to anti-angiogenic therapy used in the clinic.

High Expression of HIF-1α, BNIP3 and PI3KC3: Hypoxia-Induced Autophagy Predicts Cholangiocarcinoma Survival and Metastasis

“…Our results revealed that CoCl 2 generated a hypoxic condition and induced autophagy by increasing levels of HIF-1α, BNIP3, PI3KC3 and autophagosomal marker LC3-II in CCA cell lines. A chemical mimetic of hypoxia CoCl 2 increased autophagy has been demonstrated in several models such as in the H9c2 rat cardiomyoblast cell culture (Gallo et al, 2014) and human periodontal ligament cells (Song et al, 2012) resulting in an increasing LC3-II level that is similar to O 2 depletion induced hypoxia (Hu et al, 2012). The hypoxia induced LC3-II/LC3-I ratio has been shown that it activates autophagosome maturation (Gallo et al, 2014).…”

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

“…51,52 Previous studies have shown that HIF1A contributes to autophagy regulation in hypoxia. 20,[24][25][26][27][68][69][70] The BH3 domains of BNIP3 and BNIP3L, known HIF1A targets, disrupt the BCL2-BECN1 complex, releasing more BECN1 to be involved in the autophagic process. 24 In NP cells, although the BNIP3 level was increased under hypoxia, the absence of a concomitant increase in p-BECN1 Ser93 indicated a possible lack of correlation with autophagic induction.…”

YY1-MIR372-SQSTM1 regulatory axis in autophagy

“…Since autophagy is required for the in vivo growth of tumor cells that survive and proliferate under stress conditions such as hypoxia and nutrient deficiency, we wondered whether autophagy-blocker MIR372 can inhibit tumor growth in vivo. 28,29 The xenograft nude mice model was applied to determine the effect of stably expressed MIR372 on the in vivo tumorigenecity of breast cancer cells. Indeed, the in vivo growth of MCF7 cells with stable MIR372 expression was indeed significantly slower and the tumor mass was significantly smaller and lighter ( Fig.…”