DNA mismatch repair gene MLH1 induces apoptosis in prostate cancer cells.

Shinichiro Fukuhara,Shahana Majid,Inik Chang,Takeshi Chiyomaru,Guoren Deng,Ankurpreet Gill,Hiroaki Shiina,Hiroshi Hirata,Darryn K Wong,Yuichiro Tanaka,Soichiro Yamamura,Norio Nonomura,Yozo Mitsui,Rajvir Dahiya,Sharanjot Saini

doi:10.18632/oncotarget.2315

Abstract

Mismatch repair (MMR) enzymes have been shown to be deficient in prostate cancer (PCa). MMR can influence the regulation of tumor development in various cancers but their role on PCa has not been investigated. The aim of the present study was to determine the functional effects of the mutL-homolog 1 (MLH1) gene on growth of PCa cells. The DU145 cell line has been established as MLH1-deficient and thus, this cell line was utilized to determine effects of MLH1 by gene expression. Lack of MLH1 protein expression was confirmed by Western blotting in DU145 cells whereas levels were high in normal PWR-1E and RWPE-1 prostatic cells. MLH1-expressing stable transfectant DU145 cells were then created to characterize the effects this MMR gene has on various growth properties. Expression of MLH1 resulted in decreased cell proliferation, migration and invasion properties. Lack of cell growth in vivo also indicated a tumor suppressive effect by MLH1. Interestingly, MLH1 caused an increase in apoptosis along with phosphorylated c-Abl, and treatment with MLH1 siRNAs countered this effect. Furthermore, inhibition of c-Abl with STI571 also abrogated the effect on apoptosis caused by MLH1. These results demonstrate MLH1 protects against PCa development by inducing c-Abl-mediated apoptosis.

Highlights

Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer death among males in the United States [1]
Absence of mutL-homolog 1 (MLH1) protein in DU145 cells led us to examine whether re-expressing MLH1 affects the growth of these cells
MTS assay show that cell proliferation was reduced over 30% after 48 hours in DU145 cells expressing MLH1 compared to vector control (P

Summary

Introduction

Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer death among males in the United States [1]. It is estimated that in 2014, there will be 233,000 new cases and 29,480 deaths due to PCa [1]. PCa is a disease of aging as 1 in 43 of those aged 50 to 59, 1 in 16 aged 60 to 69, and 1 in 9 aged 70 years and older will develop invasive disease [1]. Most cases of PCa are treatable with androgen-deprivation therapy the majority of PCa recur as androgen-independent, metastatic disease that leads to death within several years. No effective therapies are available to cure androgen-independent PCa. new prognostic markers and effective treatment strategies are urgently needed

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