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Research Articles: Therapeutics, Targets, and Development

Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells

¹ Department of Medicine and ² Nutritional Sciences, University of Toronto, ³ Clinical Epidemiology Unit, Sunnybrook Health Sciences Center, and ⁴ Division of Gastroenterology, St. Michael's Hospital, Toronto, Ontario, Canada; ⁵ Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey; and ⁶ Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York

Requests for reprints: Young-In Kim, Room 7258, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada, M5S 1A8. Phone: 416-978-1183; Fax: 416-978-8765. E-mail: youngin.kim{at}utoronto.ca

Abstract

Folylpolyglutamyl synthase (FPGS) converts intracellular folates and antifolates to polyglutamates. Polyglutamylated folates and antifolates are retained in cells longer and are better substrates than their monoglutamate counterparts for enzymes involved in one-carbon transfer. FPGS modulation affects the chemosensitivity of cancer cells to antifolates, such as methotrexate, and 5-fluorouracil (5FU) by altering polyglutamylation of antifolates and specific target intracellular folate cofactors. However, this effect may be counterbalanced by FPGS modulation-induced changes in polyglutamylation of other intracellular folate cofactors and total intracellular folate pools. We generated an in vitro model of FPGS overexpression and inhibition in breast cancer cells by stably transfecting human MDA-MB-435 breast cancer cells with the sense FPGS cDNA or FPGS-targeted small interfering RNA, respectively, and investigated the effects of FPGS modulation on chemosensitivity to 5FU and methotrexate. FPGS modulation-induced changes in polyglutamylation of both antifolates and folate cofactors and in intracellular folate pools affected chemosensitivity of breast cancer cells to pemetrexed and trimetrexate whose cytotoxic effects do or do not depend on polyglutamylation, respectively, in a predictable manner. However, the effects of FPGS modulation on the chemosensitivity of breast cancer cells to 5FU and methotrexate seem to be highly complex and depend not only on polyglutamylation of a specific target intracellular folate cofactor or methotrexate, respectively, but also on total intracellular folate pools and polyglutamylation of other intracellular folate cofactors. Whether or not FPGS modulation may be an important clinical determinant of chemosensitivity of breast cancer cells to 5FU and methotrexate-based chemotherapy needs further exploration. [Mol Cancer Ther 2007;6(11):2909–20]

Grant support: Operating grant (14126) from the Canadian Institutes of Health Research (to Y.I. Kim). R.C. Cho is a recipient of a scholarship from the Natural Sciences and Engineering Research Council of Canada. P.D. Cole is a Damon Runyon-Lilly Clinical Investigator, supported in part by the Damon Runyon Cancer Research Foundation (CI-16-03). B.A. Kamen is an American Cancer Society Professor.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Presented in part at the 2006 American Association for Cancer Research meeting, April 1–5, 2006, Washington, DC, and published in abstract form in the Proceedings of the American Association for Cancer Research 2006; 47: Abstract 2149.

Received 7/18/07; accepted 9/14/07.