Knockdown of Etv5 enhances nitric oxide production and caspase-independent cell death in pancreatic INS-1E-cells

The transcription factor ETV5 is widely expressed and regulates diverse genes including a whole string related to obesity and diabetes. ETV5 is involved in the regulation of glucose-induced insulin secretion from ?-cells and its pancreatic loss increases the severity of pancreatitis. On this account, we investigated whether ETV5 is regulated by nutritional states and whether it plays a role in proliferation and survival from cellular stress using rat INS-1E ?-cells and doxycycline-inducible shRNA knockdown of Etv5. Neither low or high glucose conditions nor serum deprivation had an effect on ETV5 expression in normal INS-1E ?-cells while streptozotocin and palmitate time- and dose-dependently induced its expression to significant levels after 24h. Etv5 knockdown did not change proliferation but significantly further enhanced streptozotocin- and palmitate-mediated loss of viability. In this context, Etv5 knockdown neither had an impact on the expression of the proliferative and anti-apoptotic proteins NUPR1 and RET nor on caspases-3 and -7 activation levels. Instead, Etv5 knockdown was associated with increased basal nitric oxide production and augmented caspase-independent cell death upon exposure to streptozotocin and palmitate. In conclusion, ETV5 seems to limit nitric oxide production and may thereby play a role in the protection of ?-cells from necrosis upon certain cellular stresses.