Targeting Glutamine Metabolism in Prostate Cancer.

Abstract

Glutamine is a conditionally essential amino acid important for cancer cell proliferation through intermediary metabolism leading to de novo synthesis of purine and pyrimidine nucleotides, hexosamine biosytnehsis, fatty acid synthesis through reductive carboxylation, maintenance of redox homeostasis, glutathione synthesis, production of non-essential amino acids, and mitochondrial oxidative phosphorylation. Prostate cancer has increasingly been characterized as a tumor type that is heavily dependent on glutamine for growth and survival. In this review, we highlight the preclinical evidence that supports a relationship between glutamine signaling and prostate cancer progression. We focus on the regulation of glutamine metabolism in prostate cancer through key pathways involving the androgen receptor pathway, MYC, and the PTEN/PI3K/mTOR pathway. We end with a discussion on considerations for translation of targeting glutamine metabolism as a therapeutic strategy to manage prostate cancer. Here, it is important to understand that the tumor microenvironment also plays a role in facilitating glutamine signaling and resultant prostate cancer growth. The druggability of prostate cancer glutamine metabolism is more readily achievable with our greater understanding of tumor metabolism and the advent of selective glutaminase inhibitors that have proven safe and tolerable in early-phase clinical trials.