ABSTRACT
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.
Subject(s)
Adenoma, Oxyphilic/drug therapy , Adenoma, Oxyphilic/genetics , Aminopyridines/pharmacology , Antineoplastic Agents/pharmacology , Electron Transport Complex I/antagonists & inhibitors , Electron Transport Complex I/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Metformin/pharmacology , Pyrroles/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/genetics , Drosophila , Female , Gene Knockout Techniques , HCT116 Cells , Humans , Macrophages/immunology , Mice , Mice, Knockout , Mice, Nude , NADH Dehydrogenase/genetics , Neovascularization, Pathologic/pathology , Xenograft Model Antitumor AssaysABSTRACT
In the last 10 years, studies of energetic metabolism in different tumors clearly indicate that the definition of Warburg effect, i.e. the glycolytic shift cells undergo upon transformation, ought to be revisited considering the metabolic plasticity of cancer cells. In fact, recent findings show that the shift from glycolysis to re-established oxidative metabolism is required for certain steps of tumor progression, suggesting that mitochondrial function and, in particular, respiratory complex I are crucial for metabolic and hypoxic adaptation. Based on these evidences, complex I can be considered a lethality target for potential anticancer strategies. In conclusion, in this mini review we summarize and discuss why it is not paradoxical to develop pharmacological and genome editing approaches to target complex I as novel adjuvant therapies for cancer treatment. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.