An investigation of the role of cytosolic superoxide dismutase (SOD1) on the C-X-C chemokine receptor type 4 (CXCR4)-mediated signal transduction in prostate cancer cells

Abstract

Prostate cancer (PCa) is associated with high rates of cancer spread, or metastasis, the process that accounts for up to 90% of cancer-related deaths. CXCR4, a chemokine G protein-coupled receptor (GPCR), and its ligand CXCL12, are highly expressed in both PCa tissue, and common locations of metastasis, including the lymph nodes, lungs and bone. Multiple studies have demonstrated the importance of the CXCR4/CXCL12 signaling axis in cancer progression, specifically due to its role in cell survival, proliferation and migration. In addition, antioxidants are implicated in modulating cell survival through the scavenging of free oxygen radicals. Our lab has shown that the antioxidant superoxide dismutase (SOD1) interacts with CXCR4. The goal of this project was to determine to what extent this interaction modulates PCa metastasis. We have shown that the level of interaction between CXCR4 and SOD1 in PC3 prostate cancer cells is increased by CXCL12 stimulation in normoxic, but not in hypoxic conditions. Our work suggests that SOD1 can prevent apoptosis in normoxic, but not in hypoxic conditions. We also found that, unexpectedly, CXCR4 signaling seems to switch from coupling with both G?i and G?q in normal conditions to favouring G?q coupling in hypoxia, regardless of SOD1 expression level. This result was corroborated by the fact that the G?i inhibitor pertussis toxin (PTX) was able to ablate CXCR4-mediated chemotaxis in normal, but not in hypoxic conditions. Overall, this project was able to characterize the effects of the interaction between SOD1 and CXCR4 on the regulation of certain pathways involved in the metastatic transition. Future work involves investigating second messenger levels to confirm the G protein switch that occurs in hypoxia and the use of animal models for in vivo work. The eventual aim of this project is to exploit this protein interaction to develop a therapeutic that can help prevent cancer-related deaths.