CpG hypermethylation of MDR1 gene contributes to the pathogenesis and progression of human prostate cancer

Multidrug resistance 1 (MDR1) gene encodes for P-glycoprotein (P-gp), a Mr 170,000 transmembrane calcium-dependent efflux pump that is inactivated in prostate cancer. We hypothesize that inactivation of the MDR1 gene through CpG methylation contributes to the pathogenesis and progression of prostate...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2004-09, Vol.64 (17), p.5956-5962
Main Authors: ENOKIDA, Hideki, SHIINA, Hiroaki, VERMA, Mukesh, KAWAHARA, Motoshi, NAKAGAWA, Masayuki, KANE, Christopher J, CARROLL, Peter R, DAHIYA, Rajvir, IGAWA, Mikio, OGISHIMA, Tatsuya, KAWAKAMI, Toshifumi, BASSETT, William W, ANAST, Jason W, LI, Long-Cheng, URAKAMI, Shinji, TERASHIMA, Masaharu
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Antineoplastic agents
Apoptosis - genetics
Azacitidine - analogs & derivatives
Azacitidine - pharmacology
Base Sequence
Biological and medical sciences
Cell Division - genetics
CpG Islands - genetics
Disease Progression
DNA Methylation
Gene Expression Regulation, Neoplastic - drug effects
Gene Expression Regulation, Neoplastic - genetics
Gene Silencing
Genes, MDR - drug effects
Genes, MDR - genetics
Humans
Male
Medical sciences
Middle Aged
Molecular Sequence Data
Pharmacology. Drug treatments
Promoter Regions, Genetic
Prostatic Hyperplasia - genetics
Prostatic Hyperplasia - metabolism
Prostatic Hyperplasia - pathology
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
Tumors
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Summary:Multidrug resistance 1 (MDR1) gene encodes for P-glycoprotein (P-gp), a Mr 170,000 transmembrane calcium-dependent efflux pump that is inactivated in prostate cancer. We hypothesize that inactivation of the MDR1 gene through CpG methylation contributes to the pathogenesis and progression of prostate cancer. To test this hypothesis, CpG methylation status of the MDR1 promoter and its correlation with clinicopathological findings were evaluated in 177 prostate cancer samples and 69 benign prostate hypertrophy (BPH) samples. Cellular proliferation index and apoptotic index were determined by proliferating cell nuclear antigen (PCNA) and single-strand DNA immunostaining, respectively. After 5-aza-2'-deoxycytidine treatment, increased expression of MDR1 mRNA transcript was found in prostate cancer cell lines (DU145, DuPro, and ND1). MDR1 methylation frequency was significantly higher in prostate cancer samples compared with BPH samples (54.8 versus 11.6%, respectively, P < 0.001). Logistic regression analysis revealed that PC patients are 11.5 times more likely to have MDR1 methylation than BPH patients (95% confidence interval 4.87-27.0) and that MDR1 methylation is independent of the age. Significant correlation of MDR1 methylation was observed with high pT category (P < 0.001), high Gleason sum (P = 0.008), high preoperative prostate-specific antigen (P = 0.01), and advancing pathological features. In addition, PCNA-labeling index were significantly higher in methylation-specific PCR (MSP)-positive than in MSP-negative prostate cancer samples (P = 0.048). In contrast, no significant difference in apoptotic index was found between MSP-positive and -negative prostate cancer samples. These findings suggest that CpG hypermethylation of MDR1 promoter is a frequent event in prostate cancer and is related to disease progression via increased cell proliferation in prostate cancer cells.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-04-0081