Abstract 1100: Functional genomics to investigate the genetic determinants of cell death induced by oxidative stresses

Increased oxidative stress in the tumor microenvironments is a prominent stress that many tumor cells need to cope with during oncogenesis. The stress depletes intracellular glutathione, increases reactive oxygen species, and finally triggers cell death in tumors. Despite its importance during oncogenesis, the genetic determinants and the cell death mechanisms under oxidative stress remain poorly defined. Here, we applied a genome-wide siRNA screen to oxidative-stress-induced cell death. Candidate genes were identified if the silencing could rescue cell death under oxidative stresses. The identified candidate genes are prioritized by the magnitude of rescue and the consistency among different siRNAs that target the same gene. Selected top hits were further functionally validated using independent siRNAs and chemicals in multiple cancer cell types. To further understand the functional aspects of these genes, we also analyzed the transcriptional and metabolomic response to oxidative stresses. By these functional genomics approach, we found that: 1) The Integrated Stress Response (ISR) is provoked by oxidative stresses to mediate cell death. Therefore, inhibition of IRE1-splicing activity, which is one of the major branches of ISR pathway, could abolish oxidative-stress-induced cell death. 2) Surprisingly, inhibition of multiple component of mTORC1 signaling, including mTOR itself, could rescue oxidative-stress-induced cell death. While further investigation is still in progress...

Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Ding, C.-K. C., Tang, X., Kim, S. Y., Chi, J.-T. A. Tags: Molecular and Cellular Biology Source Type: research