Abstract CN05-03: Modulating ER stress-induced autophagy to cancer control

Abstract

Abstract CN05-03 Two major protein degradation systems are present in the cell, the ubiquitin proteasome system and the autophagy machinery. Inhibition of proteasome can activates autophagy, suggesting that the two systems are functionally coupled. Autophagy plays a compensatory role as suppression of autophagy promotes the accumulation of polyubiquitinated protein aggregates. Autophagy is likely activated in response to endoplasmic reticulum stress caused by misfolded proteins during proteasome inhibition. Indeed, direct disturbing ER environment with chemicals such as A23187, tunicamycin, thapsigargin and brefeldin A, can induce autophagy. Suppression of a major unfolded protein response pathway mediated by IRE1 by either gene deletion or RNAi dramatically suppresses the activation of autophagy by proteasome inhibitors or ER stress inducers. Interestingly, JNK but not XBP-1, both of which are the known downstream targets of IRE1, seems to participate in autophagy induction by proteasome inhibitors. Autophagy induced under these conditions is important for controlling endoplasmic reticulum stress and for reducing cell death in cancer cells. Thus a combined use of proteasome inhibitors and autophagy inhibitors enhances tumor cell death both in vitro and in vivo. Notably, this enhanced toxicity was not observed in non-transformed normal cells, suggesting that the impact of autophagy on cell survival during endoplasmic reticulum stress is likely contingent on the oncogenic status of cells. These findings indicate that blocking both autophagic and proteasomal degradation systems could be a novel and selective strategy for cancer control via the regulation of ER stress. Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN05-03.