Krishna B Singh1, Eun-Ryeong Hahm1, Shivendra V Singh1,2. 1. Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 2. UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Abstract
AIM: Leelamine (LLM) inhibits growth of human prostate cancer cells but the underlying mechanism is not fully understood. The present study was undertaken to determine the effect of LLM on cMyc, which is overexpressed in a subset of human prostate cancers. METHODS: The effect of LLM on cMyc expression and activity was determined by western blotting/confocal microscopy and luciferase reporter assay, respectively. A transgenic mouse model of prostate cancer (Hi-Myc) was used to determine chemopreventive efficacy of LLM. RESULTS: Exposure of androgen sensitive (LNCaP) and castration-resistant (22Rv1) human prostate cancer cells to LLM resulted in downregulation of protein and mRNA levels of cMyc. Overexpression of cMyc partially attenuated LLM-mediated inhibition of colony formation, cell viability, and cell migration in 22Rv1 and/or PC-3 cells. LLM treatment decreased protein levels of cMyc targets (e.g., lactate dehydrogenase), however, overexpression of cMyc did not attenuate these effects. A trend for a decrease in expression level of cMyc protein was discernible in 22Rv1 xenografts from LLM-treated mice compared with control mice. The LLM treatment (10 mg/kg body weight, 5 times/week) was well-tolerated by Hi-Myc transgenic mice. The incidence of high-grade prostatic intraepithelial neoplasia, adenocarcinoma in situ, and microinvasion was lower in LLM-treated Hi-Myc mice but the difference was not statistically significant. CONCLUSION: The present study reveals that LLM inhibits cMyc expression in human prostate cancer cells in vitro but concentrations higher than 10 mg/kg may be required to achieve chemoprevention of prostate cancer.
AIM: Leelamine (LLM) inhibits growth of human prostate cancer cells but the underlying mechanism is not fully understood. The present study was undertaken to determine the effect of LLM on cMyc, which is overexpressed in a subset of human prostate cancers. METHODS: The effect of LLM on cMyc expression and activity was determined by western blotting/confocal microscopy and luciferase reporter assay, respectively. A transgenic mouse model of prostate cancer (Hi-Myc) was used to determine chemopreventive efficacy of LLM. RESULTS: Exposure of androgen sensitive (LNCaP) and castration-resistant (22Rv1) human prostate cancer cells to LLM resulted in downregulation of protein and mRNA levels of cMyc. Overexpression of cMyc partially attenuated LLM-mediated inhibition of colony formation, cell viability, and cell migration in 22Rv1 and/or PC-3 cells. LLM treatment decreased protein levels of cMyc targets (e.g., lactate dehydrogenase), however, overexpression of cMyc did not attenuate these effects. A trend for a decrease in expression level of cMyc protein was discernible in 22Rv1 xenografts from LLM-treated mice compared with control mice. The LLM treatment (10 mg/kg body weight, 5 times/week) was well-tolerated by Hi-Myc transgenic mice. The incidence of high-grade prostatic intraepithelial neoplasia, adenocarcinoma in situ, and microinvasion was lower in LLM-treated Hi-Myc mice but the difference was not statistically significant. CONCLUSION: The present study reveals that LLM inhibits cMyc expression in human prostate cancer cells in vitro but concentrations higher than 10 mg/kg may be required to achieve chemoprevention of prostate cancer.
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