title: Folic acid mediates activation of the pro-oncogene STAT3 via the Folate Receptor alpha.
abstract: The signal transducer and activator of transcription 3 (STAT3) is a well-described pro-oncogene found constitutively activated in several cancer types. Folates are B vitamins that, when taken up by cells through the Reduced Folate Carrier (RFC), are essential for normal cell growth and replication. Many cancer cells overexpress a glycophosphatidylinositol (GPI)-anchored Folate Receptor α (FRα). The function of FRα in cancer cells is still poorly described, and it has been suggested that transport of folate is not its primary function in these cells. We show here that folic acid and folinic acid can activate STAT3 through FRα in a Janus Kinase (JAK)-dependent manner, and we demonstrate that gp130 functions as a transducing receptor for this signalling. Moreover, folic acid can promote dose dependent cell proliferation in FRα-positive HeLa cells, but not in FRα-negative HEK293 cells. After folic acid treatment of HeLa cells, up-regulation of the STAT3 responsive genes Cyclin A2 and Vascular Endothelial Growth Factor (VEGF) were verified by qRT-PCR. The identification of this FRα-STAT3 signal transduction pathway activated by folic and folinic acid contributes to the understanding of the involvement of folic acid in preventing neural tube defects as well as in tumour growth. Previously, the role of folates in these diseases has been attributed to their roles as one-carbon unit donors following endocytosis into the cell. Our finding that folic acid can activate STAT3 via FRα adds complexity to the established roles of B9 vitamins in cancer and neural tube defects.
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Mariann F
authors.initials: MF
authors.lastname: Hansen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Eva
authors.initials: E
authors.lastname: Greibe
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Signe
authors.initials: S
authors.lastname: Skovbjerg
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rohde
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Anders C M
authors.initials: AC
authors.lastname: Kristensen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Trine R
authors.initials: TR
authors.lastname: Jensen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Stentoft
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Karina H
authors.initials: KH
authors.lastname: Kjær
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Camilla S
authors.initials: CS
authors.lastname: Kronborg
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: pmm@mbg.au.dk.
authors.forename: Pia M
authors.initials: PM
authors.lastname: Martensen
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D056751:Cyclin A2 / Q000235:genetics / Q000378:metabolism; D058975:Folate Receptor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005492:Folic Acid / Q000494:pharmacology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D002955:Leucovorin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D056751:Cyclin A2; D058975:Folate Receptor 1; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D042461:Vascular Endothelial Growth Factor A; D005492:Folic Acid; D053612:Janus Kinases; D002955:Leucovorin
keywords: Folate Receptor; Folic acid; STAT3; Vitamin B9; gp130