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Review
. 2021 Dec 31;14(1):191.
doi: 10.3390/cancers14010191.

Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer

Adrianne Wallace-Povirk  1   2 , Zhanjun Hou  1   2 , Md Junayed Nayeen  3 , Aleem Gangjee  3 , Larry H Matherly  1   2   4
Affiliations
Review

Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer

Adrianne Wallace-Povirk et al. Cancers (Basel). .

Abstract

New therapies are urgently needed for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy. To identify new approaches for targeting EOC, metabolic vulnerabilities must be discovered and strategies for the selective delivery of therapeutic agents must be established. Folate receptor (FR) α and the proton-coupled folate transporter (PCFT) are expressed in the majority of EOCs. FRβ is expressed on tumor-associated macrophages, a major infiltrating immune population in EOC. One-carbon (C1) metabolism is partitioned between the cytosol and mitochondria and is important for the synthesis of nucleotides, amino acids, glutathione, and other critical metabolites. Novel inhibitors are being developed with the potential for therapeutic targeting of tumors via FRs and the PCFT, as well as for inhibiting C1 metabolism. In this review, we summarize these exciting new developments in targeted therapies for both tumors and the tumor microenvironment in EOC.

Keywords: epithelial ovarian cancer; folate; folate receptor; folate transport; one-carbon metabolism; proton-coupled folate transporter; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
Structures of inhibitors of C1 metabolism. Panel (A): structures are shown for the dual SHMT1 and SHMT2 inhibitors SHIN1 and SHIN2 [150,151], the MTHFD2 inhibitor DS18561882 [152], as well as pemetrexed [137] and CT900 (BGC945, ONX0801) [26] (both principally thymidylate synthase inhibitors). Panel (B): structures are shown for pyrrolo[2,3-d]pyrimidine GARFTase inhibitors, AGF17 [145], AGF23 [145], AGF94 [147], AGF154 [148], AGF278 [149], and AGF283 [149], as well as the pyrrolo[3,2-d]pyrimidine antifolate AGF347 [153], which acts as a multitargeted inhibitor of SHMT2 in the mitochondria and of SHMT1, GARFTase, and ATIC in the cytosol.
Figure 1
Figure 1
Folate transport and C1 metabolism. A schematic is shown depicting cellular uptake by facilitative transport via RFC or PCFT or by endocytosis via FRα. Intracellular folates are metabolized to polyglutamate conjugates. Folate “monoglutamates” are transported into the mitochondria by SLC25A32. In the mitochondria, serine is catabolized by sequential SHMT2, MTHFD2/L, and MTHFD1L through which the C1 moiety from serine C3 is incorporated into formate, thus providing C1 units for cellular biosynthesis in the cytosol. Abbreviations are as follows: 10-CHO-THF, 10-formyl tetrahydrofolate; 5,10-me-THF, 5,10-methylene tetrahydrofolate; AICAR, 5-aminoimidazole-4-carboxamide; ALDH1L2, aldehyde dehydrogenase 1 family member L2; ATIC, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase; DHF, dihydrofolate; DHFR, dihydrofolate reductase; FAICAR, formyl 5-aminoimidazole-4-carboxamide ribonucleotide; fGAR, formyl glycinamide ribonucleotide; FPGS, folylpoly-γ-glutamate synthetase; GAR, glycinamide ribonucleotide; GARFTase, glycinamide ribonucleotide formyltransferase; GR, glutathione reductase; GS, glutathione synthetase; GSH, glutathione; MTFMT, methionyl tRNA formyltransferase; MTHFD1, methylenetetrahydrofolate dehydrogenase 1; MTHFD2(L), methylene tetrahydrofolate dehydrogenase 2(-like); MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; PCFT, proton-coupled folate transporter; PGs, polyglutamates; PRPP, phosphoribosyl pyrophosphate; RFC, reduced folate carrier; SAM, S-adenosylmethionine; SHMT1/2, serine hydroxymethyltransferase 1/2; THF, tetrahydrofolate; and TS, thymidylate synthase.
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