Ators. Modulation of TRP channels could perturb Ca2+ homeostasis, resulting in subsequent cell death. In hepatocellular carcinoma cells, TRPC6 is actually a unfavorable regulator of cell death induced by doxorubicin, hypoxia, and ionizing radiation36. In contrast to TRPC6, TRPV4 is positively 65836-72-8 Autophagy regulated pronounced cell death throughLiu et al. Cell Death and Disease (2019)ten:Web page 11 ofapoptosis, oncosis, or necrosis in breast cancer or melanoma cells11,37. Additionally, sustained exposure to TRPV4 agonists has been shown to evoke dose-dependent apoptosis of retinal ganglion cells and hippocampal neuronal cells38. Nonetheless, we discovered that TRPV4 silencing by siRNA enhanced apoptosis in human colon cancer cells and decreased resistance to chemotherapy-induced apoptosis. However, TRPV4 antagonists induced apoptosis in human hepatocellular carcinoma24. Therefore, TRPV4 could execute two apparently opposite functions by either promoting or inhibiting apoptosis inside a cell type-dependent manner. Autophagy is a selfdegradative procedure that is linked with either cell survival or cell death39. Considerable evidence has emerged that the functional regulation of TRP channels affected the autophagic process40. TRPM3 is necessary for oncogenic autophagy under starvation conditions in clear cell renal cell carcinoma41. TRPM2-induced Ca2+ influx inhibited autophagy in response to oxidative strain, causing the cells to become much more susceptible to damage42. TRPV4 inhibited apoptosis via induction of autophagy in response to TGF-1 stimulation in rat hepatic stellate cells43. In this study, we observed that TRPV4 played a part in the induction of autophagic process. Depending on the cellular context and signals, autophagy has dual functions since it has been involved in stimulating either cell survival or inducing cell death44. In our study, disruption of TRPV4 silencing-mediated autophagy by knockdown autophagy-related genes elevated colon cancer cell viability. These results indicated that autophagy induced by TRPV4 silencing acted as a cell death mechanism. The AKT signaling pathway regulates many typical cellular functions which are also critical for tumorigenesis. Hyperactivation of AKT is related with increased cell growth, proliferation, cellular energy metabolism, and resistance to apoptosis45. In earlier reports, AKT is involved in TRPV4-mediated signaling in polycystic kidneys of rats25 and in hippocampal neuronal cells46. Nevertheless, the underlying mechanism of TRPV4-regulated cell growth will not be absolutely understood. We discovered that the blockade of TRPV4 decreased protein levels of cyclin D1 and cyclin D3, which had been regulated by translation inside the mTOR signaling pathway. This suggested that TRPV4 could be involved in regulation in the mTOR signaling pathway. mTOR is usually a critical downstream effector of AKT, which regulates several fundamental cell processes from protein synthesis to autophagy47. mTOR largely regulates protein synthesis through phosphorylation of two key effectors, S6K and 4E-BP48. In this study, we