Abstract 2715: Cell cycle regulated mitophagy: a key step at the G1/S metabolic checkpoint

Abstract

Abstract How tumor cells coordinate their high demand for biosynthetic processes with nutrient availability, proliferation rate and oxidative stress tolerance is still not completely understood. We recently showed that highly proliferating cells, whether normal or tumorigenic, display different metabolic requirements throughout the cell cycle, in term of glucose and glutamine utilization. The role of autophagy in cancer cells is still debated, but recent evidence pointed to its involvement in the regulation of cellular bioenergetics and nutrients utilization. To investigate autophagy regulation during cancer cells proliferation and to characterize in detail the metabolic behaviour associated with tumor cell proliferation in the different phases of the cell cycle, we used synchronized HeLaS3, a human epithelial carcinoma cell line. Treatment of the cells with a double thymidine block (DTB) results in an arrest at the G1/S boundary and the possibility to study their progression through a complete division cycle. Here we show that in the highly proliferating HeLaS3 cancer cells basal autophagy is a cell cycle regulated phenomenon, responsible for mitochondria quality control and that it plays an essential role at the G1/S checkpoint. Both general autophagy genetic inhibition and mitophagy pharmacological inhibition with Mdivi-1 during cell cycle progression lead the cells to enter faster in S phase. However, probably due to the high levels of oxidative stress dictated by their proliferation rate, autophagy-incompetent cells start to accumulate insulted and less functional mitochondria. Autophagy is likely to be involved in the induction of resistance mechanisms to treatments in different types cancers. Because of this, there is an increased interest in the possibility to use inhibitors of the autophagic pathways as adjuvants for current anti-tumor therapies. Further investigations of the mechanisms here described will be of importance to elucidate whether drugs which inhibit autophagy may be a viable and effective approach in combination with chemotherapy for the treatment of highly proliferating cancers. Citation Format: Daniela Annibali. Cell cycle regulated mitophagy: a key step at the G1/S metabolic checkpoint. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2715.