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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  ;  Yuichiro Tanaka 
 ONCOTARGET , Vol.5(22) : 11297-11307, 2014 
Journal Title
Issue Date
Adaptor Proteins, Signal Transducing/biosynthesis ; Adaptor Proteins, Signal Transducing/genetics* ; Animals ; Apoptosis/genetics ; Benzamides/pharmacology ; Cell Line, Tumor ; DNA Mismatch Repair* ; Heterografts ; Humans ; Imatinib Mesylate ; Male ; Mice ; Mice, Nude ; MutL Protein Homolog 1 ; Nuclear Proteins/biosynthesis ; Nuclear Proteins/genetics* ; Phosphorylation ; Piperazines/pharmacology ; Prostatic Neoplasms/genetics* ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology* ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-abl/antagonists & inhibitors ; Proto-Oncogene Proteins c-abl/metabolism ; Pyrimidines/pharmacology ; Transfection
MLH1 ; c-Abl ; apoptosis ; prostate cancer
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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2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Chang, In Ik(장인익)
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