Abstract A12: Erk2 phosphorylates Drp1 to promote mitochondrial fission and Ras-driven tumor growth.

Abstract

Abstract Oncogenic Ras mutations lead to activation of several downstream effector pathways that promote a tumorigenic phenotype. As targeting Ras directly has proven difficult, a great deal of effort has been expended trying to understand these downstream effector pathways and the biological processes that underlie their pro-tumorigenic activity. Several of the processes affected by aberrant Ras signaling, including apoptosis, metabolic reprogramming and proliferation, are tightly linked to mitochondrial function. Furthermore, each of these processes can be affected by changes in mitochondrial dynamics. As such, we hypothesized that altering the balance of mitochondrial fusion and fission might be a mechanism through which Ras promotes the phenotypes associated with tumor progression and thus might represent an attractive new target for the treatment of Ras-driven cancers. Here, we show that expression of oncogenic Ras leads to an increase in mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits Ras-driven tumor growth. Mechanistically, this Ras-driven mitochondrial fission occurs through activation of the MAP Kinase pathway, which promotes fission through Erk2-mediated phosphorylation of Drp1 on Serine 616. Furthermore, Drp1 phospho-S616 levels are increased in pancreatic cancer tissues and cell lines and inhibition of this phosphorylation is sufficient to block Ras-mediated mitochondrial fission and Ras-induced tumor growth. Collectively, these data suggest that the mitochondrial fission machinery may be a novel target for treating Ras-driven malignancies. Citation Format: David Kashatus. Erk2 phosphorylates Drp1 to promote mitochondrial fission and Ras-driven tumor growth.. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A12. doi: 10.1158/1557-3125.RASONC14-A12