The folate receptor α is frequently overexpressed in osteosarcoma samples and plays a role in the uptake of the physiologic substrate 5-methyltetrahydrofolate Journal Article
| Authors: | Yang, R.; Kolb, E. A.; Qin, J.; Chou, A.; Sowers, R.; Hoang, B.; Healey, J. H.; Huvos, A. G.; Meyers, P. A.; Gorlick, R. |
| Article Title: | The folate receptor α is frequently overexpressed in osteosarcoma samples and plays a role in the uptake of the physiologic substrate 5-methyltetrahydrofolate |
| Abstract: | 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. © 2007 American Association for Cancer Research. |
| Keywords: | osteosarcoma; controlled study; protein expression; bone neoplasms; unclassified drug; nonhuman; methotrexate; cell proliferation; animal cell; mouse; animals; ovary cancer; antimetabolites, antineoplastic; animal experiment; animal model; tumor xenograft; drug resistance, neoplasm; xenograft model antitumor assays; cell line, tumor; drug uptake; rna, messenger; folinic acid; carrier proteins; real time polymerase chain reaction; folic acid; folic acid antagonists; cell transport; drug transport; receptors, cell surface; folate receptor alpha; folate receptor; 5 methyltetrahydrofolic acid; active transport; tetrahydrofolates |
| Journal Title: | Clinical Cancer Research |
| Volume: | 13 |
| Issue: | 9 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2007-05-01 |
| Start Page: | 2557 |
| End Page: | 2567 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-06-1343 |
| PUBMED: | 17473184 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 9" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus" |
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