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Regulation of Prostaglandin Transporters in Colorectal Neoplasia

Authors' Affiliations: Departments of ¹ Cancer Biology and ² Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ³ Department of Medicine, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee

Requests for reprints: Raymond N. DuBois, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 118, Houston, TX 77030. Phone: 713-745-4495; Fax: 713-745-1812; E-mail: rdubois{at}mdanderson.org.

Abstract

Prostaglandin E₂ (PGE₂) promotes cancer progression by affecting cell proliferation, apoptosis, angiogenesis, and the immune response. It has been reported that PGE₂ is transported or passes through the cell membrane via prostaglandin-specific transporters including the prostaglandin transporter (PGT, an influx transporter) and the multidrug resistance-associated protein 4 (an efflux transporter). PGT can facilitate the removal of PGE₂ from the extracellular milieu by transporting it into the cell, where 15-hydroxyprostaglandin dehydrogenase (15-PGDH) then oxidizes PGE₂ into 15-keto PGE₂. We previously reported that 15-PGDH expression is reduced in most colorectal cancers, indicating the tumor suppressor role of this gene. In the present study, we show that PGT expression is also decreased (whereas multidrug resistance-associated protein 4 expression is elevated) in human colorectal cancer specimens (compared with expression in normal mucosa) and in colorectal cancer cell lines. Furthermore, we found that PGT expression decreased in premalignant adenomas in Apc^min mice and was partially restored (in human colorectal cancer cell lines) by treatment with a DNA demethylating agent or histone deacetylase inhibitor. Forced PGT overexpression in vitro reduced extracellular PGE₂ levels and increased intracellular levels of its catabolic product 15-keto PGE₂. Our data suggest that the existing model to explain increased PGE₂ in colorectal neoplasia should be modified to include the novel mechanism of coordinated up- and down-regulation of genes involved in PGE₂ transport.

Commentary

Colorectal Neoplasia Goes with the Flow: Prostaglandin Transport and Termination

Sanford D. Markowitz
Cancer Prevention Research 2008 0: 1940-6207.CAPR-08-0009v1. [Abstract]