Abstract
PURPOSE: To examine the effects of voluntary wheel running on tumor growth and explore potential intratumoral molecular pathways responsible for the beneficial effects of voluntary wheel running on tumor formation and progression in a mouse model of castration-resistant prostate cancer (CRPC). METHODS: Male immunodeficient mice (SCID) were castrated and subcutaneously inoculated with human CWR-22RV1 cancer cells to construct CRPC xenograft model before assigned to either voluntary wheel running (VWR) or sedentary (SED) group ( n = 6/group). Tumor size was measured and calculated throughout the study. After 3 wk, tumor tissues were collected. mRNA expression of markers of DNA replication, androgen receptor (AR) signaling, and mitochondrial dynamics was determined by quantitative real-time polymerase chain reaction. Protein expression of mitochondrial dynamics was determined by Western blotting. Finally, transcriptomics analysis was performed using the tumor tissues. RESULTS: Voluntary wheel running resulted in smaller tumor volume at the initial stage and attenuated tumor progression throughout the time course ( P < 0.05). The reduction of tumor volume in the VWR group coincided with lower mRNA expression of DNA replication markers ( MCM2 , MCM6 , and MCM7 ), AR signaling ( ELOVL5 and FKBP5 ), and regulatory proteins of mitochondrial fission (Drp1 and Fis1) and fusion (MFN1 and OPA1) when compared with the SED group ( P < 0.05). RNA sequencing data further revealed that pathways related to angiogenesis, extracellular matrix formation, and endothelial cell proliferation were downregulated. CONCLUSIONS: Three weeks of voluntary wheel running was effective in delaying tumor formation and progression, which coincided with reduced transcription of DNA replication, AR signaling targets, and mitochondrial dynamics. We further identified a downregulation in molecular pathways related to angiogenesis that may be responsible for the delayed tumor formation and progression by voluntary wheel running.