Circulating IGF-1 promotes prostate adenocarcinoma via FOXO3A/BIM signaling in a double-transgenic mouse model.
Shuang WangNing WangBin YuMingxing CaoYanlong WangYuqi GuoYanli ZhangPing ZhangXiao YuShujing WangLi ZengBin LiangXin LiYingjie WuPublished in: Oncogene (2019)
High circulating insulin-like growth factor-1 (IGF-1) levels increase the risk of prostate cancer. However, whether circulating IGF-1 levels directly aggravate prostate cancer remains elusive. In this study, we crossed a transgenic prostate adenocarcinoma mouse model, Hi-Myc mice, with a liver-specific IGF-1 transgenic mouse model (HIT) to increase their circulating IGF-1 levels to investigate the impact of the elevated circulating IGF-1 on prostate cancer development in vivo. The Hi-Myc/HIT mice had increased incidence and invasiveness of prostate cancer. IGF-1 elevation led to the accumulation of FOXO3A in the cytosol of prostate tumor cells and downregulation of its target gene Bim, which resulted in the apoptosis inhibition and prostate cancer overgrowth. The differential expressions of IGF-1R, FOXO3A, and BIM in the benign versus malignant prostate tissues supported a negative association between the FOXO3A/BIM axis and IGF-1R expression in human prostate adenocarcinoma. Our findings suggest that targeting the IGF-1/FOXO3A/BIM signaling axis could be an attractive strategy for prostate cancer prevention or treatment.
Keyphrases
- prostate cancer
- pi k akt
- radical prostatectomy
- binding protein
- signaling pathway
- mouse model
- growth hormone
- transcription factor
- cell cycle arrest
- cell proliferation
- squamous cell carcinoma
- poor prognosis
- cell death
- endothelial cells
- gene expression
- oxidative stress
- metabolic syndrome
- benign prostatic hyperplasia
- locally advanced
- adipose tissue
- radiation therapy
- cancer therapy
- insulin resistance