Prostate-specific membrane antigen (PSMA), androgen modulation, folic acid, and high-grade prostate cancer: An intriguing nexus needing attention

Prostate cancer is the most common cancer, excluding skin cancer, diagnosed among men in the US. Autopsy studies confirm the high prevalence of indolent prostate cancers starting in the third decade of life. There are lifestyle and therapeutic factors that might be facilitating the transformation of indolent to high-grade cancers throughout life. Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is highly expressed on prostate cancer cells and has diagnostic, prognostic and therapeutic implications. Emerging evidence has elucidated many of its biologic functions, including folate acquisition from the gut, transporting unmetabolized circulating folic acid into prostate cancer cells, involvement in physiologic and neoplastic angiogenesis and redirecting cell survival signaling pathways. Folates are utilized by the prostate for various aspects of reproductive biology. Synthetic oxidized folic acid has been used in grain and cereal fortification in the US since 1998; as a result, folate levels have more than doubled, and most individuals exhibit unmetabolized folic acid in the circulation. In fact, folic acid from fortified foods and supplements is the main driver of folate levels in the population. However, folic acid is a double-edged sword and can support nucleotide synthesis and prostate cancer cell proliferation. As such, the promotion of high-grade prostate cancer by folic acid, but not natural folates, has been evidenced in prospective trials. Ironically, androgen deprivation therapy (ADT), used in the treatment of prostate cancer, leads to increases in both PSMA expression and folate levels. Therefore, we hypothesize that avoiding folic acid intake from fortified foods and supplements will decrease the risk of high-grade prostate cancer and decrease prostate cancer progression, particularly among men undergoing treatment with ADT. Moreover, the nexus of PSMA, folic acid, androgen modulation and high-grade prostate cancer is discussed, along with practical and therapeutic implications. Finally, questions are raised which should spur interest in research that might translate into a reduction in high-grade prostate cancer.