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The folate receptor alpha is frequently overexpressed in osteosarcoma samples and plays a role in the uptake of the physiologic substrate 5-methyltetrahydrofolate.

Yang R, Kolb EA, Qin J, Chou A, Sowers R, Hoang B, Healey JH, Huvos AG, Meyers PA, Gorlick R

Department of Pediatrics and Molecular Pharmacology, The Albert Einstein College of Medicine, The Children's Hospital at Montefiore, Bronx, New York 10467, USA.

PURPOSE: Two major systems exist for folate cell entry: the reduced folate carrier (RFC) and the folate receptor (FR). Although defective RFC-mediated transport was frequently identified as a mechanism of methotrexate (MTX) resistance in osteosarcoma, the status of FR and its role in this disease are unknown. EXPERIMENTAL DESIGN: mRNA for FR alpha was measured in 107 osteosarcoma specimens using quantitative reverse transcription-PCR and was related to RFC expression. The effect of FR alpha overexpression on MTX resistance and natural folate uptake was studied using FR alpha non-expressing osteosarcoma 143B cells transfected with FR alpha cDNA in comparison with those transfected with sense or antisense RFC in the same genetic background. RESULTS: Eighty-four samples (78.5%) had detectable FR alpha mRNA, and 29.9% had higher levels than the ovarian cancer cell line SKOV-3. No correlation was found between mRNA levels of FR alpha and RFC (r(2)=0.002). FR alpha overexpression had minor effects on the transport of MTX and sensitivity to this drug. Among the transfected 143B sublines, only the 143B-FR alpha was able to uptake 5-methyltetrahydrofolate when the extracellular concentration was reduced to 2 nmol/L, which conferred a growth advantage in physiologic folate concentrations compared with vector-only-transfected cells. Importantly, this was not similarly achieved by RFC overexpression. CONCLUSIONS: This study suggests that FR alpha plays a role in the uptake of 5-methyltetrahydrofolate when the concentration gradient is insufficient for RFC-mediated transport. FR alpha overexpression is unlikely secondary to the decreased RFC expression in osteosarcoma.

Published 2 May 2007 in Clin Cancer Res, 13(9): 2557-67.
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