The Folate Receptor α Is Frequently Overexpressed in Osteosarcoma Samples and Plays a Role in the Uptake of the Physiologic Substrate 5-Methyltetrahydrofolate
| Autor: | Paul A. Meyers, Alexander J. Chou, Richard Gorlick, Jing Qin, Rui Yang, John H. Healey, Rebecca Sowers, Andrew G. Huvos, Bang H. Hoang, E. Anders Kolb |
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| Rok vydání: | 2007 |
| Předmět: |
Antimetabolites
Antineoplastic Cancer Research medicine.medical_specialty Bone Neoplasms Receptors Cell Surface Biology Folic Acid Cell Line Tumor Internal medicine Sense (molecular biology) medicine Extracellular Animals Humans RNA Messenger Receptor Tetrahydrofolates Osteosarcoma Messenger RNA Folate Receptors GPI-Anchored Transfection medicine.disease Xenograft Model Antitumor Assays Methotrexate Endocrinology Oncology Drug Resistance Neoplasm Folate receptor Cell culture Cancer research Folic Acid Antagonists Carrier Proteins |
| Zdroj: | Clinical Cancer Research. 13:2557-2567 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-06-1343 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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