title: DNA mismatch repair gene MLH1 induces apoptosis in prostate cancer cells.
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.
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Urology, University of California, San Francisco, California, United States of America. Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Fukuhara
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Oral Biology,Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Urology, University of California, San Francisco, California, United States of America. Department of Urology, Shimane University Faculty of Medicine, Izumo, Japan.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Mitsui
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Urology, University of California, San Francisco, California, United States of America. Department of Urology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiyomaru
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Sharanjot
authors.initials: S
authors.lastname: Saini
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America.
authors.forename: Ankurpreet
authors.initials: A
authors.lastname: Gill
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America.
authors.forename: Darryn K
authors.initials: DK
authors.lastname: Wong
authors.affiliation: Department of Urology, Shimane University Faculty of Medicine, Izumo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiina
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
authors.affiliation: Department of Surgery/Urology, Veterans Affairs Medical Center, San Francisco, California, United States of America. Department of Urology, University of California, San Francisco, California, United States of America.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D053843:DNA Mismatch Repair; D064593:Heterografts; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D000070957:MutL Protein Homolog 1