Oncotarget

Research Papers:

DNA mismatch repair gene MLH1 induces apoptosis in prostate cancer cells

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

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Oncotarget. 2014; 5:11297-11307. https://doi.org/10.18632/oncotarget.2315

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Abstract

Shinichiro Fukuhara1,2,3,*, Inik Chang1,4,*, Yozo Mitsui1,2,5, Takeshi Chiyomaru1,2,6, Soichiro Yamamura1,2, Shahana Majid1,2, Sharanjot Saini1,2, Hiroshi Hirata1,2, Guoren Deng1,2, Ankurpreet Gill1, Darryn K. Wong1, Hiroaki Shiina5, Norio Nonomura3, Rajvir Dahiya1,2 and Yuichiro Tanaka1,2

1 Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America

2 Department of Urology, University of California, San Francisco, California, United States of America

3 Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan

4 Department of Oral Biology,Yonsei University College of Dentistry, Seoul, Korea

5 Department of Urology, Shimane University Faculty of Medicine, Izumo, Japan

6 Department of Urology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

* These authors contributed equally to this work

Correspondence:

Yuichiro Tanaka, email:

Keywords: MLH1, c-Abl, apoptosis, prostate cancer

Received: May 29, 2014 Accepted: August 05, 2014 Published: August 06, 2014

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.


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