Folate transporter dynamics and therapy with classic and tumor-targeted antifolates

Abstract There are three major folate uptake systems in human tissues and tumors, including the reduced folate carrier (RFC), folate receptors (FRs) and proton-coupled folate transporter (PCFT). We studied the functional interrelationships among these systems for the novel tumor-targeted antifolates...

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Autores principales:	Carrie O’Connor, Adrianne Wallace-Povirk, Changwen Ning, Josephine Frühauf, Nian Tong, Aleem Gangjee, Larry H. Matherly, Zhanjun Hou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dd3e87cff5634115a13acaae3166b8b6
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spelling	oai:doaj.org-article:dd3e87cff5634115a13acaae3166b8b62021-12-02T13:18:01ZFolate transporter dynamics and therapy with classic and tumor-targeted antifolates10.1038/s41598-021-85818-x2045-2322https://doaj.org/article/dd3e87cff5634115a13acaae3166b8b62021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85818-xhttps://doaj.org/toc/2045-2322Abstract There are three major folate uptake systems in human tissues and tumors, including the reduced folate carrier (RFC), folate receptors (FRs) and proton-coupled folate transporter (PCFT). We studied the functional interrelationships among these systems for the novel tumor-targeted antifolates AGF94 (transported by PCFT and FRs but not RFC) and AGF102 (selective for FRs) versus the classic antifolates pemetrexed, methotrexate and PT523 (variously transported by FRs, PCFT and RFC). We engineered HeLa cell models to express FRα or RFC under control of a tetracycline-inducible promoter with or without constitutive PCFT. We showed that cellular accumulations of extracellular folates were determined by the type and levels of the major folate transporters, with PCFT and RFC prevailing over FRα, depending on expression levels and pH. Based on patterns of cell proliferation in the presence of the inhibitors, we established transport redundancy for RFC and PCFT in pemetrexed uptake, and for PCFT and FRα in AGF94 uptake; uptake by PCFT predominated for pemetrexed and FRα for AGF94. For methotrexate and PT523, uptake by RFC predominated even in the presence of PCFT or FRα. For both classic (methotrexate, PT523) and FRα-targeted (AGF102) antifolates, anti-proliferative activities were antagonized by PCFT, likely due to its robust activity in mediating folate accumulation. Collectively, our findings describe a previously unrecognized interplay among the major folate transport systems that depends on transporter levels and extracellular pH, and that determines their contributions to the uptake and anti-tumor efficacies of targeted and untargeted antifolates.Carrie O’ConnorAdrianne Wallace-PovirkChangwen NingJosephine FrühaufNian TongAleem GangjeeLarry H. MatherlyZhanjun HouNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Carrie O’Connor Adrianne Wallace-Povirk Changwen Ning Josephine Frühauf Nian Tong Aleem Gangjee Larry H. Matherly Zhanjun Hou Folate transporter dynamics and therapy with classic and tumor-targeted antifolates
description	Abstract There are three major folate uptake systems in human tissues and tumors, including the reduced folate carrier (RFC), folate receptors (FRs) and proton-coupled folate transporter (PCFT). We studied the functional interrelationships among these systems for the novel tumor-targeted antifolates AGF94 (transported by PCFT and FRs but not RFC) and AGF102 (selective for FRs) versus the classic antifolates pemetrexed, methotrexate and PT523 (variously transported by FRs, PCFT and RFC). We engineered HeLa cell models to express FRα or RFC under control of a tetracycline-inducible promoter with or without constitutive PCFT. We showed that cellular accumulations of extracellular folates were determined by the type and levels of the major folate transporters, with PCFT and RFC prevailing over FRα, depending on expression levels and pH. Based on patterns of cell proliferation in the presence of the inhibitors, we established transport redundancy for RFC and PCFT in pemetrexed uptake, and for PCFT and FRα in AGF94 uptake; uptake by PCFT predominated for pemetrexed and FRα for AGF94. For methotrexate and PT523, uptake by RFC predominated even in the presence of PCFT or FRα. For both classic (methotrexate, PT523) and FRα-targeted (AGF102) antifolates, anti-proliferative activities were antagonized by PCFT, likely due to its robust activity in mediating folate accumulation. Collectively, our findings describe a previously unrecognized interplay among the major folate transport systems that depends on transporter levels and extracellular pH, and that determines their contributions to the uptake and anti-tumor efficacies of targeted and untargeted antifolates.
format	article
author	Carrie O’Connor Adrianne Wallace-Povirk Changwen Ning Josephine Frühauf Nian Tong Aleem Gangjee Larry H. Matherly Zhanjun Hou
author_facet	Carrie O’Connor Adrianne Wallace-Povirk Changwen Ning Josephine Frühauf Nian Tong Aleem Gangjee Larry H. Matherly Zhanjun Hou
author_sort	Carrie O’Connor
title	Folate transporter dynamics and therapy with classic and tumor-targeted antifolates
title_short	Folate transporter dynamics and therapy with classic and tumor-targeted antifolates
title_full	Folate transporter dynamics and therapy with classic and tumor-targeted antifolates
title_fullStr	Folate transporter dynamics and therapy with classic and tumor-targeted antifolates
title_full_unstemmed	Folate transporter dynamics and therapy with classic and tumor-targeted antifolates
title_sort	folate transporter dynamics and therapy with classic and tumor-targeted antifolates
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/dd3e87cff5634115a13acaae3166b8b6
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Folate transporter dynamics and therapy with classic and tumor-targeted antifolates

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