The folate receptor alpha 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 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.

• Authors: Rui Yang, E Anders Kolb, Jing Qin, Alexander Chou, Rebecca Sowers, Bang Hoang, John H Healey, Andrew G Huvos, Paul A Meyers, Richard Gorlick
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 9 Pg. 2557-67 (May 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17473184 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Carrier Proteins
• Folate Receptors, GPI-Anchored
• Folic Acid Antagonists
• RNA, Messenger
• Receptors, Cell Surface
• Tetrahydrofolates
• Folic Acid
• 5-methyltetrahydrofolate
• Methotrexate

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Bone Neoplasms (genetics, metabolism)
• Carrier Proteins (analysis, genetics, metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Folate Receptors, GPI-Anchored
• Folic Acid (metabolism)
• Folic Acid Antagonists (pharmacology)
• Humans
• Methotrexate (pharmacology)
• Osteosarcoma (genetics, metabolism)
• RNA, Messenger (metabolism)
• Receptors, Cell Surface (analysis, genetics, metabolism)
• Tetrahydrofolates (metabolism)
• Xenograft Model Antitumor Assays