The Rab27A effector MYRIP as a regulator of survival in non-small cell lung cancer cells

Background: Personalising therapy for non-small cell lung cancer has been validated as an effective treatment paradigm. Somatic gene alterations confer sensitivity to inhibition of growth survival pathways irrespective of underlying resistance to chemotherapeutic agents, and enables efficient activation of BCL-2 family-dependent pro-apoptotic signalling. In platinum resistant cancers this signalling is blocked, however the intrinsic pathway remains sensitive to exogenous BH3 death signals. Methods: Microarray profiling coupled to focused RNAi screening was used to reveal those resistance genes involved in derepression of proapoptotic BCL-2 family proteins. Analysis of the effect of MYRIP expression on survival was generated from studying 6 NSCLC datasets from Gene Expression Omnibus which were paired with survival time and status information. The toxic effect of MYRIP depletion on NSCLC and non-cancerous lung cells was determined by cell viability and clonogenic assays. Apoptotic induction was examined by caspase and PARP cleavage experiments, and fractionation of mitochondrial proteins. FACS analysis was used to examine effects on cell cycle. Results: MYRIP/Slac2c, a gene hitherto associated with vesicle trafficking but not apoptosis, was overexpressed in platinum resistant NSCLC cells. In particular, cisplatin resistant cells expressed a heavier protein isoform of MYRIP which appeared to be associated with the mitochondria. Silencing of MYRIP induced BIM and BAX/BAK-dependent mitochondrial apoptosis which was selective for NSCLC, but not non-cancerous lung cells. In addition, loss of MYRIP induced S-phase arrest. Conclusions: Overexpression of MYRIP is an independent, poor prognostic factor suggesting that targeting these genes may be therapeutically relevant. In summary, MYRIP exhibits a previously unknown survival function associated with suppression of pro-apoptotic BCL-2 family proteins and maintenance of cancer cell proliferation and survival.