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

DOI

10.1038/s41598-021-85818-x

Authors

Carrie O'Connor, Departments of Oncology, Wayne State University School of Medicine, 421 E. Canfield, Detroit, MI, 48201, USA.
Adrianne Wallace-Povirk, Departments of Oncology, Wayne State University School of Medicine, 421 E. Canfield, Detroit, MI, 48201, USA.
Changwen Ning, Departments of Oncology, Wayne State University School of Medicine, 421 E. Canfield, Detroit, MI, 48201, USA.
Josephine Frühauf, Departments of Oncology, Wayne State University School of Medicine, 421 E. Canfield, Detroit, MI, 48201, USA.
Nian Tong, Division of Medicinal Chemistry, Duquesne University, Pittsburgh, PA, USA.
Aleem Gangjee, Division of Medicinal Chemistry, Duquesne University, Pittsburgh, PA, USA.
Larry H. Matherly, Departments of Oncology, Wayne State University School of Medicine, 421 E. Canfield, Detroit, MI, 48201, USA. matherly@karmanos.org.
Zhanjun Hou, Departments of Oncology, Wayne State University School of Medicine, 421 E. Canfield, Detroit, MI, 48201, USA. houz@karmanos.org.

Document Type

Journal Article

Publication Date

3-18-2021

Publication Title

Scientific reports

Volume

11

Issue

1

First Page

6389

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.

Open Access

Gold

Repository Citation

O'Connor, C., Wallace-Povirk, A., Ning, C., Frühauf, J., Tong, N., Gangjee, A., Matherly, L. H., & Hou, Z. (2021). Folate transporter dynamics and therapy with classic and tumor-targeted antifolates. Scientific reports, 11 (1), 6389. https://doi.org/10.1038/s41598-021-85818-x