Cancer Cells Evade Stress-Induced Apoptosis by Promoting HSP70-Dependent Clearance of Stress Granules

SIMPLE SUMMARY: The formation of stress granules is a cellular mechanism to limit protein synthesis and avoid the production of unfolded proteins in stressed cells. In the present study, we found that prolonged stress caused persistent stress granules, leading to cell death in normal cells. However, cancer cells can evade stress-induced cell death by promoting HSP70-dependent clearance of stress granules. In other words, the dynamics of stress granules determine the cell status during prolonged stress. Our work provides insight into tumorigenesis in stressed cells. It also suggests a new approach to potentially treating cancers by modulating the dynamics of stress granules. ABSTRACT: The formation of stress granules (SG) is regarded as a cellular mechanism to temporarily limit protein synthesis and prevent the unfolding of proteins in stressed cells. It has been noted that SG formation can promote the survival of stressed cells. Paradoxically, however, persistent SGs could cause cell death. The underlying molecular mechanism that affects the relationship between SG dynamics and cellular states is not fully understood. Here we found that SG dynamics in cancer cells differ significantly from those in normal cells. Specifically, prolonged stress caused the formation of persistent SGs and consequently resulted in apoptosis in the normal cells. By contrast, cancer cells resolved SGs and survived the prolonged stress. Regarding the mechanism, the knockdown of HSP70 or the inhibition of the HSP70s’ ATPase activity caused defective SG clearance, leading to apoptosis in otherwise healthy cancer cells. On the other hand, the knockout of G3BPs to block the formation of SGs allowed cancer cells to escape from the HSP70 inhibition-induced apoptosis. Given the observation that SG dynamics were barely affected by the inhibition of autophagy or proteasome, we propose that SG dynamics are regulated mainly by HSP70-mediated refolding of the unfolded proteins or their removal from SGs. As a result, cancer cells evade stress-induced apoptosis by promoting the HSP70-dependent SG clearance.