Functional role of DNA mismatch repair gene PMS2 in prostate cancer cells.

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

doi:10.18632/oncotarget.3854

Abstract

DNA mismatch repair (MMR) enzymes act as proofreading complexes that maintains genomic integrity and MMR-deficient cells show an increased mutation rate. MMR has also been shown to influence cell signaling and the regulation of tumor development. MMR consists of various genes and includes post-meiotic segregation (PMS) 2 which is a vital component of mutL-alpha. In prostate, the functional role of this gene has never been reported and in this study, our aim was to investigate the effect of PMS2 on growth properties of prostate cancer (PCa) cells. Previous studies have shown PMS2 to be deficient in DU145 cells and this lack of expression was confirmed by Western blotting whereas normal prostatic PWR-1E and RWPE-1 cells expressed this gene. PMS2 effects on various growth properties of DU145 were then determined by creating stable gene transfectants. Interestingly, PMS2 caused decreased cell proliferation, migration, invasion, and in vivo growth; and increased apoptosis as compared to vector control. We further analyzed genes affected by PMS2 expression and observe the apoptosis-related TMS1 gene to be significantly upregulated whereas anti-apoptotic BCL2A1 was downregulated. These results demonstrate a functional role for PMS2 to protect against PCa progression by enhancing apoptosis of PCa cells.

Highlights

Prostate cancer (PCa) ranked as the most frequently diagnosed malignancy among men in the United States of America with an estimated 233, 000 new incidences in the Year 2014 [1]
MTS assay showed that cell proliferation was reduced 41% in clone #1 and 29% in clone #2 after 72 hours in DU145 cells expressing PMS2 compared to vector control (P < 0.01) (Figure 2B)
Wound healing assay demonstrated significant inhibition of cell migration in PMS2-stable compared with vector-transfected DU145 cells after 24 hours (47% closure clone #1 and 42% closure clone #2 versus 73% closure for control, P < 0.01) (Figure 2C)

Summary

Introduction

Prostate cancer (PCa) ranked as the most frequently diagnosed malignancy among men in the United States of America with an estimated 233, 000 new incidences in the Year 2014 [1]. PCa is generally treatable with androgen-deprivation therapy there is a high recurrence to an androgen-independent and metastatic state of this cancer that leads to death within several years. A factor that can lead to PCa is DNA mismatch mutations and to overcome their harmful effects, the cell has the DNA mismatch repair (MMR) system that is able to correct these lesions. Deficiencies in the MMR pathway can result in higher rates of mutation or genetic instability that can cause defects in genes that regulate cell proliferation and death [2], thereby increasing susceptibility to cancers. MMR is vital for proper cellular function and health of the individual

Objectives

Methods

Results

Conclusion