Paradoxical Impact of Two Folate Receptors, FRα and RFC, in Ovarian Cancer: Effect on Cell Proliferation, Invasion and Clinical Outcome

Abstract

Despite being an essential vitamin, folate has been implicated to enhance tumor growth, as evidenced by reports on overexpression of folate receptor alpha (FRα) in carcinomas. The role of another folate transporter, reduced folate carrier (RFC), is largely unknown. This study investigated the roles of folate, FRα and RFC in ovarian cancers. We demonstrated FRα mRNA and protein overexpression and reduced RFC expression in association with FRα gene amplification and RFC promoter hypermethylation, respectively. FRα overexpression was associated with tumor progression while RFC expression incurred a favorable clinical outcome. Such reciprocal expression pattern was also observed in ovarian cancer cell lines. Folate was shown to promote cancer cell proliferation, migration and invasion in vitro, and down-regulate E-cadherin expression. This effect was blocked after either stable knockdown of FRα or ectopic overexpression of RFC. This hitherto unreported phenomenon suggests that, RFC can serve as a balancing partner of FRα and confer a protective effect in patients with high FRα-expressing ovarian carcinomas, as evidenced by their prolonged overall and disease-free survivals. In conclusion, we report on the paradoxical impact of FRα (putative oncogenic) and RFC (putative tumor suppressive) in human malignancies. FRα and RFC may potentially be explored as therapeutic target or prognostic marker respectively. We recommend caution and additional research on folate supplements in cancer patients.

Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation

“…In many cancers, FRs are overexpressed, and this is associated with neoplastic progression and poor prognosis (Kelemen, 2006). FRα promotes proliferation, migration, and invasiveness of SKOV-3 ovarian cancer cells, which have high-level FRα expression; while surprisingly, RFC acts oppositely to reduce cell proliferation, migration, and invasiveness (Siu et al, 2012). Notably, FRα only contributes 20–30% of the uptake of folate in SKOV-3 and four other ovarian cancer cell lines, while RFC is responsible for ~70% of their folate uptake (Corona et al, 1998).…”

Preparation, cytotoxicity, and in vivo antitumor efficacy of ¹¹¹In-labeled modular nanotransporters

“…We have chosen Laemmli SDS-PAGE instead of the usually used instant thin layer chromatography to evaluate the labeling yields, since this method not only provides the data about the percentage of unreacted 111 In that migrates immediately before bromophenol blue on the gel, but also demonstrates the integrity of protein molecule after labeling. cytotoxicity studies 23 HeLa or SK-OV-3 (both FR-positive), 24,25 and A431 or U87MG. wtEGFR (both EGFR-positive) 15 In-NOTA-MNT (0.03-9.5 MBq/mL) or 111 In-EDTA as a control (0.3-9.5 MBq/mL) were added.…”

Therapeutic targets and new directions for antibodies developed for ovarian cancer

“…It is overexpressed in 80–90% of EOCs 16 . The level of FRα expression on cancer cells, has been shown to correlate with the histologic grade and stage of ovarian cancer 17-19 . Overexpression is significantly higher in serous ovarian carcinoma than in mucinous carcinomas and other epithelial histotypes.…”