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

Rui Yang, E. Anders Kolb, Jing Qin, Alexander Chou, Rebecca Sowers, Bang Hoang, John H. Healey, Andrew G. Huvos, Paul A. Meyers, Richard Gorlick

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40 Scopus citations


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 FRα was measured in 107 osteosarcoma specimens using quantitative reverse transcription-PCR and was related to RFC expression. The effect of FRα overexpression on MTX resistance and natural folate uptake was studied using FRα non-expressing osteosarcoma 143B cells transfected with FRα cDNA in comparison with those transfected with sense or antisense RFC in the same genetic background. Results: Eighty-four samples (78.5%) had detectable FRα mRNA, and 29.9% had higher levels than the ovarian cancer cell line SKOV-3. No correlation was found between mRNA levels of FRα and RFC (r2 = 0.002). FRα overexpression had minor effects on the transport of MTX and sensitivity to this drug. Among the transfected 143B sublines, only the 143B-FRα 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 FRα plays a role in the uptake of 5-methyltetrahydrofolate when the concentration gradient is insufficient for RFC-mediated transport. FRα overexpression is unlikely secondary to the decreased RFC expression in osteosarcoma.

Original languageEnglish (US)
Pages (from-to)2557-2567
Number of pages11
JournalClinical Cancer Research
Issue number9
StatePublished - May 1 2007


ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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