Atorvastatin Enhances Inhibitory Effects of Irradiation on Tumor Growth by Reducing MSH2 Expression Both in Prostate Cancer Cells and Xenograft Tumor Models.

Abstract

Prostate cancer (PCa) is the fourth most common tumor in males. This study aimed to investigate effects of atorvastatin (AS) on PCa cells proliferation and clarify the associated mechanisms. PCa cell lines were cultured and treated with irradiation (IR) (4 Gy), AS (6 μg/ml), transfected with Bcl-2 siRNA, and then divided into different groups. Xenograft tumor mouse model was established. Bcl-2 and MSH2 gene transcription and protein expression were evaluated using RT-PCR assay and western blot assay. Plate clone formation assay was employed to examine colony formation. MTT assay was used to detect cell viabilities. Flow cytometry analysis was utilized to verify apoptosis. Co-immunoprecipitation and immuno-fluorescence assay were used to identify interaction between Bcl-2 and MSH2. IR significantly reduced colony formation, enhanced Bcl-2 and reduced MSH2 gene transcription in PCa cells compared to un-treated cells (p<0.05). AS significantly strengthened radio-therapeutic effects of IR on colony formation, decreased cell apoptosis and increased Bcl-2 gene transcription/protein expression in PCa cells compared to single IR treatment cells (p<0.05). AS combining IR down-regulated MSH2 gene transcription/protein expression in PCa cells compared to single IR treatment cells (p<0.05). Bcl-2 interacted with MSH2 both in PCa cells and tumor tissues administrating with AS. AS enhanced reductive effects of IR on tumor size of Xenograft tumor mice. Atorvastatin administration enhanced inhibitory effects of IR either on PCa cells or tumor size of Xenograft tumor mice. The inhibitory effects of atorvastatin were mediated by reducing MSH2 expression and triggering interaction between Bcl-2 and MSH2, both in vitro and in vivo levels.