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Overexpression of OATP1B3 Confers Apoptotic Resistance in Colon Cancer

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky; Departments of ² Surgery and ³ Pathology, Vanderbilt University, Nashville, Tennessee; ⁴ Division of Oncology and ⁵ Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri; ⁶ Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; and ⁷ Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada

Requests for reprints: Wooin Lee, Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536. Phone: 859-257-6065; Fax: 615-243-7602; E-mail: wooin.lee{at}uky.edu.

Key Words: apoptosis • colon cancer • OATP1B3

Organic anion transporting polypeptide 1B3 (OATP1B3, SLCO1B3) is normally expressed in hepatocytes. In this study, we showed frequent overexpression of OATP1B3 in colorectal adenocarcinomas. Quantitative reverse transcription-PCR analysis of 17 colon tumors indicated tumoral overexpression of OATP1B3 by 100-fold, compared with 20 normal colon samples (P < 0.0001). Using immunohistochemistry on a tissue microarray containing 93 evaluable colon tumor specimens, we detected immunostaining of OATP1B3 in 75 colon adenocarcinomas (81%) and no immunostaining in normal samples. To determine the functional effects of OATP1B3 expression on drug-induced apoptosis, we used camptothecin and oxaliplatin on a panel of colorectal cancer cell lines stably overexpressing OATP1B3. The results indicated that OATP1B3 overexpression enhanced cell survival in RKO, HCT-8, and HCT116^p53+/+ cells that harbor wild-type p53 but not in Caco-2 and HCT116^p53–/– cells that lack p53, compared with the respective empty vector controls (P < 0.01). The terminal deoxynucleotidyl transferase-mediated nick-end labeling assay confirmed that HCT116^p53+/+ cells overexpressing OATP1B3 had significantly lower apoptotic levels compared with empty vector control (P < 0.001). The overexpression of OATP1B3 reduced the transcriptional activity of p53, with subsequent reductions in transcript and protein levels of its downstream transcription targets (P21WAF1 and PUMA). Overexpression of a point mutation (G583E) variant of OATP1B3 lacking transport activity did not confer an antiapoptotic effect or affect p53 transcriptional activity, suggesting that the antiapoptotic effect of OATP1B3 may be associated with its transport activity. Taken together, our results suggest that OATP1B3 overexpression in colorectal cancer cells may provide a survival advantage by altering p53-dependent pathways. [Cancer Res 2008;68(24):10315–23]