The role of glutamine metabolism in castration-resistant prostate cancer

Abstract

Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.

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“…In our analyses, an augmented expression of SLC19A1 in breast cancer correlates with an unfavorable prognosis 69 . The protein product of PPAT acts as a crucial enzyme, pacing purine synthesis and, in tandem with GLS1, oversees the metabolic trajectory of glutamine 70 . Its heightened expression pivots the conversion of glutamine to glutamate, a precursor vital for tumor cell proliferation 71 .…”

“…69 The protein product of PPAT acts as a crucial enzyme, pacing purine synthesis and, in tandem with GLS1, oversees the metabolic trajectory of glutamine. 70 Its heightened expression pivots the conversion of glutamine to glutamate, a precursor vital for tumor cell proliferation. 71 The G6PD gene encodes for an enzyme pivotal to the pentose phosphate pathway, underscoring its significance in glucose and glutamine metabolism.…”

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“…In addition to the effects of classic hormones, evidence from genetic, bioinformatics and molecular biological studies suggests that abnormalities in amino acid metabolism play crucial roles at various stages of prostatic carcinogenesis and tumour progression [ 6 – 8 ]. Abnormal amino acid metabolism can promote the development of CRPC [ 9 ]. Targeting the amino acid metabolism network in tumour cells inhibits prostate cancer cell growth and increases chemosensitivity [ 10 ].…”

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“…Glutaminolysis also acts as an anaplerotic source by providing carbon to the TCA cycle, while simultaneously contributing nitrogen for nucleotide synthesis. The relevance of glutamine metabolism in PCa progression and the potential clinical implications of targeting glutamine metabolism have already been comprehensively addressed elsewhere [ 35 , 36 ].…”