Protein-Dependent Activation of the Unfolded Protein Response (UPR) Enables Prostate Cancer Development and a Druggable Target for Advance Prostate Cancer Therapy
Abstract
My long-term career goal is to become an outstanding independent prostate cancer surgeon and researcher with my own lab at a respected academic institute. This physician training award will provide me the technical training, conceptual knowledge, and salary support during my initial career development at the University of California, San Francisco. The research outlined in this proposal will be vital for helping us understand the role of the unfolded protein response in prostate tumorigenesis and progression into advance disease. Even with new generations of antiandrogen therapies, their durability and effectiveness are limited in men with castrate-resistant prostate cancer, and they eventually succumbed to the disease. There is an urgent need to explore new therapies that target cancer cells survival mechanism. Since correct protein folding requires coordinated balance of protein synthesis, normal intracellular pH, and normal metabolite levels, incorrect or misfolded proteins accumulate in the setting of stress and subsequently enter apoptosis. One hallmark of cancer cells is their ability to adapt to these cellular stresses and continue proliferation. The unfolded protein response (UPR) is one of the survival stress responses employed by cancer cells to maintain their survival in response to increased protein synthesis and metabolic activities induced by hyperactivation of oncogenes or loss of tumor suppressor genes, changes in intracellular pH level or DNA damage induced by chemotherapy. In contrast, normal cells rarely activate the UPR. We hypothesize that prostate cancer initiation and maintenance, at least in part, depends on protein synthesis-dependent activation of the UPR. Targeting the UPR reveals a specific vulnerability in cancer cells that offers a tremendous opportunity for therapeutic intervention. To understand how oncogenic insults that drive global protein synthesis also induce survival adaptation, we have employed a novel genetic mouse model with PTEN loss coupled to MYC overexpression in the prostate gland. We have observed that the inducible expression of Myc in the prostate synergizes with PTEN loss leading to enhanced PIN formation and activation of the UPR pathway, suggesting cooperation between MYC overexpression and PTEN loss in tumor initiation, which in turn activates the UPR pathway in vivo. In addition, we have recapitulated our in vivo data using human prostate epithelial cells that exhibit activation of the 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 increased cell death and decreased clonogenic potential in transformed cells but not in normal cells. These findings reveal a critical role of the UPR in ensuring prostate cancer cell survival through adaptation to stress and serve as a promising opportunity for the development of therapies that target this vulnerability of transformed cells. In this proposal, I will test UPR inhibitors in a preclinical trial utilizing our in vivo PTEN loss model with or without MYC overexpression. My second aim is to look at the specific mechanisms by which oncogenic lesions activate the UPR using ribosomal profiling. Lastly, I aim to study the role of UPR inhibitors as possible therapies in the setting of drug-resistant and castration-resistant prostate cancer using the MYC/PTEN loss mouse model.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510460
Entities
People
- Hao Nguyen
Organizations
- United States Army
- University of California, San Francisco