Protein Dependent Activation of the Unfolded Protein Response (UPR) Enables Prostate Cancer Development and a Druggable Target for Advance Prostate Cancer Therapy
Abstract
The acquisition of oncogenic lesions stimulates biosynthetically and bioenergetically demanding cellular processes such as protein synthesis to drive cancer cell growth and proliferation. The hijacking of these key processes by oncogenic pathways triggers cellular stress that requires an adaptive or evasive response in order for cancer cells to survive and continue proliferating. The UPR is a cellular homeostatic program engaged when an excess of unfolded/misfolded proteins accumulate within the lumen of the endoplasmic reticulum. It is carried out by three major signaling arms: PERK, IRE1, and ATF6. However, whether and how each of these distinct signaling arms of the UPR is specifically activated by deregulated protein synthesis upon oncogenic insult is poorly understood. We showed that prostate cancer initiation and maintenance, following combined loss of the PTEN tumor suppressor and overexpression of the Myc oncogene, rely on protein synthesis-dependent activation of the UPR to facilitate tumor cell survival. Specifically, we have employed a novel genetic mouse model coupling PTEN loss with MYC overexpression in the prostate and we observe that overexpression of Myc in the prostate synergizes with PTEN loss to dramatically stimulate the PERK and IRE1 signaling arms of the UPR pathway, which correlates with enhanced PIN formation and invasive carcinoma. To dissect the mechanism by which these oncogenic lesions promote UPR signaling, we employed human prostate epithelial cells overexpress MYC, harbor an shRNA targeting PTEN, or the combined overexpression of MYC and shRNA of PTEN. We demonstrate the activation of UPR arms PERK and IRE1 upon oncogenic transformation by Myc overexpression and loss of PTEN. Interestingly, blocking the cytoprotective UPR using PERK or IRE1 inhibitors resulted in a significant increase in cell death and decreased clonogenic potential in cells harboring both oncogenic lesions (MYC/PTEN), but not in normal cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2016
- Accession Number
- AD1032210
Entities
People
- Hao G. Nguyen
Organizations
- University of California, San Francisco