RESUMEN
Ras is mutated in up to 30% of cancers, including 90% of pancreatic ductal adenocarcinomas, causing it to be constitutively GTP-bound, and leading to activation of downstream effectors that promote a tumorigenic phenotype. As targeting Ras directly is difficult, there is a significant effort to understand the downstream biological processes that underlie its protumorigenic activity. Here, we show that expression of oncogenic Ras or direct activation of the MAPK pathway leads to increased mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits tumor growth. This fission is driven by Erk2-mediated phosphorylation of Drp1 on Serine 616, and both this phosphorylation and mitochondrial fragmentation are increased in human pancreatic cancer. Finally, this phosphorylation is required for Ras-associated mitochondrial fission, and its inhibition is sufficient to block xenograft growth. Collectively, these data suggest mitochondrial fission may be a target for treating MAPK-driven malignancies.
Asunto(s)
GTP Fosfohidrolasas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Dinámicas Mitocondriales , Proteínas Mitocondriales/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Neoplasias Pancreáticas/metabolismo , Animales , Benzamidas/farmacología , Línea Celular Tumoral , Difenilamina/análogos & derivados , Difenilamina/farmacología , Dinaminas , GTP Fosfohidrolasas/genética , Técnicas de Silenciamiento del Gen , Células HEK293 , Células HeLa , Humanos , Ratones , Ratones Desnudos , Proteínas Asociadas a Microtúbulos/genética , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales/genética , Neoplasias Experimentales/metabolismo , Fosforilación , Serina/metabolismo , Proteínas ras/metabolismoRESUMEN
The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the 'cancerous' translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.