Abolishing respiratory complex I decreases in vivo growth of high grade serous ovarian cancer cells and sensitizes to anti-angiogenic therapy

Abstract Targeting mitochondrial Complex I (CI) is a currently emerging anti-cancer strategy, with several enzyme inhibitors entering clinical trials. Among others, aggressive high-grade serous tubo-ovarian cancer (HGSOC) may particularly benefit from this therapeutic approach due to the scarce response to first- and second-line treatments, with consequent high mortality, such as the anti-angiogenic bevacizumab. We here show that CI represents a vulnerability in HGSOC, which can be exploited for therapeutic intervention. Indeed, ablating CI function in OV-90 HGSOC cells led to significant in vivo tumor growth decrease, smaller masses, and lower KI-67 proliferative index. This was confirmed in a switch-off system in which CI deprivation was induced during tumor progression to mimic pharmacologic treatment, suggesting this result can be achieved in growing neoplasms. We also show that abolishing CI in HGSOC cells leads to failure in stabilizing the hypoxia inducible factor-1a and to respond to hypoxia through the transcriptional activation of its target genes, ultimately lowering vascular endothelial growth factor (VEGF) and generating an immature intratumor vascular system accompanied by a decreased blood flow. Last, we demonstrate that targeting CI sets the biological basis for increased sensitivity to anti-angiogenics, as CI-deprived tumors displayed growth arrest when bevacizumab was administered, unlike their CI-competent counterpart. Our findings point to CI inhibition as a booster for anti-VEGF therapies and pave the way for combined protocols in treatment of HGSOC.