Glutamine Metabolism and Prostate Cancer
Abstract
:Simple Summary
Abstract
1. Glutamine Metabolism: An Overview
2. The Impact of Gln Metabolism on Tumor Immune Response
3. The Role of Gln Metabolism in Prostate Cancer Development and Progression
4. Targeting Glutamine Metabolism as a Strategy to Enhance Therapy Outcomes in Cancer
5. Clinical Trials Targeting Gln Metabolism in Prostate Cancer
6. The Interplay between Glutamine Metabolism and Androgen Signaling
7. The Impact of Gln Metabolism on Tumor Chemotherapy Resistance
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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No. | Genes/Pathways | Models | Selected Key Findings Related to the Topic | Refs. |
---|---|---|---|---|
1 | GLS, MYC, miR-23a/b, glutaminolysis | PCa PC3 cells and lymphoma cells | 1. MYC upregulates GLS expression by transcriptional repression of miR-23a and miR-23b; 2. Glutamine withdrawal or GLS knockdown reduces ATP and GSH levels, increases ROS, and inhibits cell proliferation. | [114] |
2 | GLS (GAC and KGA isoforms) | PCa cell lines PC3 and DU145; breast and lung cancer cell lines | 1. GAC but not KGA is localized in mitochondria; 2. The catalytic efficiency of GAC depends on the presence of inorganic phosphate. | [29] |
3 | MYC, POX/PRODH, interconnection of Gln/Pro metabolic pathways | PCa PC3 cells and lymphoma cells | 1. MYC suppresses POX/PRODH expression by upregulating miR-23b* (miR-23b [114] and miR-23b* are processed from the same transcript but differently regulated). 2. MYC induces Pro biosynthesis from Gln. | [39] |
4 | Glutamine and glucose mediated anaplerosis, mitochondrial complex I | PCa cell lines LNCaP and PC3; the transgenic adenocarcinoma of the mouse prostate (TRAMP) model | Metformin therapy enhances glutamine anaplerosis and synergizes with glutamine metabolism inhibition in cancer cells. | [137] |
5 | TXNIP, GLS, glucose uptake, glutaminolysis | PC3 cells, BPH, and PCa patient tissue samples | 1. GLS is highly expressed in PCa tissues compared to BPH; GLS levels correlate with Gleason scores and TNM stages in patients with PCa; 2. Gln and GLS positively regulate glucose uptake by inhibiting TXNIP expression. | [118] |
6 | ASTC2-mediated Gln uptake, mTORC1 pathway, E2F-regulated cell cycle genes, FA synthesis | PCa cell lines LNCaP, PC3 and DU145; PC3 xenograft murine model; PCa patient tissue samples | 1. ASCT2 expression level is increased in PCa tissues; 2. ASCT2 expression is AR-dependent; 3. ASCT2 mediates Gln uptake in PCa cells; 3. Chemical inhibition of ASCT2 decreases basal OCR and FA synthesis; 4. ASCT2 expression is essential for tumor cell growth in vitro and in vivo. | [10] |
7 | MYC, miR-205, oxidative metabolism | PCa cells PC3 and docetaxel-resistant PC3-DR cells; CAFs | Docetaxel-resistant PCa cells acquire Gln addiction | [138] |
8 | MYC, AR, and mTORC1 signaling pathways, SLC1A4, SLC1A5 | PCa cell lines LNCaP and VCaP | MYC, AR and mTORC1 oncogenic pathways regulates the expression levels of Gln transporters. | [108] |
9 | ALKBH, DNA-repair and apoptotic pathways | PC3 cells; MEF; multiple cancer cell lines; PC3 xenograft murine model | 1. Gln metabolism regulates the DNA alkylation damage repair by regulation of the α-KG-dependent ALKBH; 2. Combination of DON or CB-839 and alkylating agent MMS inhibits tumor growth in vivo. | [72] |
10 | Gln and glucose catabolism, mTORC1 pathway, AMPK, GLS (GAC and KGA isoforms), GLS2 | PCa cell lines PC3, PC3M, and non-transformed cells RWPE-2 and RWPE-1 | Metastatic PCa cells have increased Gln utilization and high sensitivity to GLS and mTORC1 inhibition. | [106] |
11 | GLS, WNT/β-catenin, cell cycle and apoptosis pathways | PCa cell lines 22Rv1, DU145, PC-3, LNCaP, and non-transformed RWPE-1 cells | GLS knockdown suppresses WNT/β-catenin pathway, inhibits cell proliferation, and induces apoptosis and cell cycle arrest. | [139] |
12 | RAS, RASAL3, TCA cycle, mitochondrial bioenergetics, PCa neuroendocrine differentiation signaling | PCa cell lines 22Rv1, C4-2B; prostatic fibroblasts derived from the patients with PCa and from murine prostates; BPH cells | 1. Epigenetic silencing of the RASAL3 gene in human prostatic CAFs results in oncogenic RAS activity and Gln synthesis and secretion; 2. CAF-derived Gln is utilized by PCa cells and induces neuroendocrine differentiation; 3. ADT promotes epigenetic silencing of RASAL3 in CAFs; 4. A high level of Gln in the blood of the patients with PCa treated with ADT correlates with therapy resistance. | [124] |
13 | PDHA1, PTEN, lipogenic genes and metabolic pathways | PCa cell lines 22Rv1, LNCaP, PC3, and DU145, PNT2C2; 22Rv1 xenograft murine model; transgenic murine models for prostate-specific deletion of PTEN and PDHA1 | 1. Gln plays an important role in de novo lipogenesis; 2. Knockdown of PDHA1 decreases the incorporation of Gln and glucose carbon into lipids and cholesterol; 3. PTEN-negative prostate cells have increased Gln carbon incorporation into citrate, fumarate, and malate compared to normal epithelial cells. | [140] |
14 | Glutaminolysis, TCA cycle, DNA damage signaling, autophagy, MYC, GLS, CSC regulation | PCa cell lines DU145, LNCaP, PC3 and their radioresistant (RR) derivatives; patient-derived cell cultures of PCa and BPH; LNCaP and DU145 xenograft murine models; blood plasma samples of PCa patients | 1. Inhibition of Gln metabolism increases oxidative stress, DNA damage and PCa sensitivity to radiotherapy; 2. Activation of ATG-mediated autophagy abrogates the radiosensitizing effect of Gln metabolism inhibition; 3. Gln metabolism regulates CSC populations by the α-KG-dependent epigenetic reprogramming; 4. A high expression of MYC and GLS genes and a high blood level of Gln correlate with a poor prognosis in PCa patients treated with radiotherapy. | [6] |
15 | Glutaminolysis, TCA cycle | PCa cell lines LNCaP and PC3; the transgenic adenocarcinoma of the mouse prostate (TRAMP) model | 1. CRPC cells possess Gln addiction; 2. The upregulation of glutaminolysis and Gln anaplerosis into the TCA cycle are characteristic of castration-resistant PCa. | [141] |
16 | ASCT2, glutaminolysis, glycolytic and lipid metabolic pathways | PCa cell lines DU145, LNCaP, and PC3; rat model | 1. CRPC cells are more Gln dependent than androgen-sensitive PCa cells; 2. DHT induce GLS and ASCT2 expression in androgen-sensitive PCa cells; 3. Inhibition of GLS with BPTES decreased PCa migration and induce cell death; 4. Anti-androgen treatment increases PCa cell sensitivity to GLS inhibition with BPTES; 5. GLS inhibition with BPTES affects glycolytic and lipid metabolism in a cell line-dependent manner. | [142] |
17 | Gln carbon and nitrogen metabolic pathways, pyrimidine synthesis, CAD, GLS, PI3K-AKT-mTOR pathway | PCa cell lines DU145, LNCaP, PC3, C4-2, C4-2MDVR and non-transformed RWPE-1 cells; PC3 and C4-2MDVR xenograft murine models; PCa patient tissue samples | 1. Gln-derived nitrogen and carbon are both required for pyrimidine synthesis in PCa cells, whereas Gln is not a main carbon source for purine synthesis; 2. CAD, a key enzyme for pyrimidine synthesis, is upregulated in PCa tissues; 3. A combination of CAD knockdown and GLS inhibition with CD-839 or knockdown has a superior inhibitory effect on PCa in vitro and in vivo than inhibition of a single protein. | [21] |
18 | GLS (GAC and KGA isoforms), glutaminolysis, AR and c-MYC signaling | PCa cell lines LNCaP, PC3, C4-2, C4-2MDVR; PCa patient tissue samples; LNCaP and PC3 xenograft murine models | 1. ADT inhibits glutaminolysis; 2. Advanced PCa and CRPC cells are highly dependent on Gln; 3. GLS isoforms are differently expressed at the different stages of PCa: KGA is highly expressed in hormone-naive PCa cells, whereas GAC is highly expressed in advanced PCa and CRPC; 4. GAC and KGA expression levels inversely correlate in PCa tissues; 5. GLS isoform switch is associated with PCa resistance to ADT; 6. Advanced PCa and CRPC cells are more sensitive to GLS inhibition with CB-839 in vitro and in vivo than androgen-dependent PCa; 7. GLS isoform switch is regulated by MYC and AR. | [121] |
19 | L-ASP, Gln transporters, Asn catabolism, cell cycle and DNA repair signaling | PCa cell lines 22Rv1, PC3, ARCaPM and its radiation-resistant derivative ARCaPM-IR; CAF; ARCaPM/CAF xenograft murine models | 1. Gln is conditionally essential for PCa cells; 2. L-ASP sensitizes PCa cells to radiotherapy through depletion of Gln; 3. Both L-ASP and Gln depletion induce cell cycle arrest and inhibit DNA repair; 4. CAF-induced PCa radioresistance can be decreased in vitro and in vivo by L-ASP. | [104] |
20 | Pro and Gln biosynthesis pathways, P5CS, ALDH18A1; TCA cycle, pyrimidine synthesis | PCa cell lines VCAP, 22Rv1, LNCaP and PC3; multiple cancer cell lines; gastric cancer patient tissue samples | 1. α-KG, Asn, and nucleotides are the key metabolites for cell survival under Gln deprivation; 2. A lowering of P5CS (ALDH18A1) expression is a common adaptation to Gln deprivation in different types of tumor cells, including PCa; 3. P5CS inhibition promotes Gln de novo synthesis. | [143] |
21 | GLS, glutaminolysis, mitochondrial bioenergetics, cell cycle and viability regulation | Docetaxel-sensitive and -resistant PCa cell lines PC3 and DU145; PCa patient tissue samples | 1. Gln deprivation and GLS inhibition with CB-839 reduces mitochondrial functions and induces apoptosis in chemotherapy-resistant and sensitive PCa cells; 2. Docetaxel-resistant PCa cells are more sensitive to the Gln metabolism inhibition than parental cells; 3. GLS expression is elevated in PCa and correlates with clinical outcomes. | [144] |
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Erb, H.H.H.; Polishchuk, N.; Stasyk, O.; Kahya, U.; Weigel, M.M.; Dubrovska, A. Glutamine Metabolism and Prostate Cancer. Cancers 2024, 16, 2871. https://doi.org/10.3390/cancers16162871
Erb HHH, Polishchuk N, Stasyk O, Kahya U, Weigel MM, Dubrovska A. Glutamine Metabolism and Prostate Cancer. Cancers. 2024; 16(16):2871. https://doi.org/10.3390/cancers16162871
Chicago/Turabian StyleErb, Holger H. H., Nikita Polishchuk, Oleh Stasyk, Uğur Kahya, Matthias M. Weigel, and Anna Dubrovska. 2024. "Glutamine Metabolism and Prostate Cancer" Cancers 16, no. 16: 2871. https://doi.org/10.3390/cancers16162871
APA StyleErb, H. H. H., Polishchuk, N., Stasyk, O., Kahya, U., Weigel, M. M., & Dubrovska, A. (2024). Glutamine Metabolism and Prostate Cancer. Cancers, 16(16), 2871. https://doi.org/10.3390/cancers16162871