Voluntary Wheel Running Alters Mitochondrial Fission Protein Drp1 In A Mouse Model Of Prostate Cancer

Prostate cancer (PCa) is the second most common cancer among men in the United States. Patients normally respond well to androgen-deprivation therapy in the initial stage. However, cancer continues to grow with low levels of testosterone and proceeds to castration-resistant prostate cancer (CRPC). Increased physical activity is known to reduce the risk of developing advanced-stage prostate cancer and mortality. Balanced mitochondrial dynamics between fission and fusion is critical in maintaining cellular function. Dysregulated mitochondrial dynamics has been linked to the progression of PCa. However, whether increased physical activity alters regulatory proteins of mitochondrial dynamics in CRPC tumors remains unknown. PURPOSE: To determine the effects of voluntary wheel running on protein expressions of regulatory markers of mitochondrial dynamics in a mouse xenograft model of CRPC. METHODS: Male immunodeficient mice were castrated and then injected subcutaneously with human PCa cells (CWR22-RV1, 1x106). Mice were either exercise trained using voluntary wheel running (EX) or remained sedentary (SED) for three weeks (n = 6/group). Tumor volumes were monitored throughout the study. 24 hours after the running wheel removal, tumor tissues were collected for immunoblot analysis to assess protein expression of regulatory markers of mitochondrial dynamics. Independent T-Test was used to test statistical differences between groups. RESULTS: Voluntary wheel running attenuated tumor growth throughout the study (P = 0.037). PCa diagnostic marker prostate-specific androgen mRNA content was reduced in EX compared to SED group (1.3 ± 0.3 vs. 1.8 ± 0.1, P = 0.004). Protein expression of Drp1, a primary regulator of mitochondrial fission, was significantly increased in EX compared to SED group (1.49 ± 0.45 vs. 1.0 ± 0.16, P = 0.026). Voluntary wheel running did not alter any other regulatory proteins responsible for mitochondrial fission (Fis1, Mid51), fusion (MFN1, MFN2, OPA1), or mitophagy (Parkin, P62, LC3B). CONCLUSION: Our data suggest that three weeks of voluntary wheel running alters mitochondrial dynamics in tumor tissues towards pro-fission state, which may result in the attenuation of tumor growth in a mouse model of CRPC. Mitochondrial dynamics may be a potential therapeutic target for treating CRPC.