Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancer strategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Here we use genetic ablation of this enzyme to induce indolence in two cancer types, and show this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha (HIF-1α). We further show that on the long run CI-deficient tumors re-adapt to their inability to respond to hypoxia, concordantly with the persistence of human oncocytomas. We demonstrate that CI-deficient tumors survive and carry out angiogenesis, despite their inability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated macrophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneous pharmacological inhibition of CI function through metformin and macrophage infiltration through PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basis for an efficient combinatorial adjuvant therapy in clinical trials.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385215PMC
http://dx.doi.org/10.1038/s41467-019-08839-1DOI Listing

Publication Analysis

Top Keywords

ci-deficient tumors
8
inducing cancer
4
cancer indolence
4
indolence targeting
4
targeting mitochondrial
4
mitochondrial complex
4
complex potentiated
4
potentiated blocking
4
blocking macrophage-mediated
4
macrophage-mediated adaptive
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!