ArticleCancer research2023
Targeting the Metabolic Enzyme PGAM2 Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting BCL2 Signaling.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 16 citations in OpenAlex.
- Article
- TRIM17 downregulation modulates CRPC progression and enzalutamide resistance by derepressing BCL2 expression via the p53-dependent and p53-independent pathways.Cell death and differentiation · 2026Article
- Transcriptional analyses identify pericyte-centered signaling programs altered by sex and brain region in Alzheimer's Disease.Communications biology · 2026Article
- Article
- Defective branched-chain amino acid catabolism promotes pulmonary fibrosis by inducing apoptosis resistance of myofibroblasts in mice.Cell communication and signaling : CCS · 2026Article
- Rewired lipid metabolism in castration-resistant prostate cancer: molecular interplay between glucose metabolism and sterol synthesis.Molecular biology reports · 2026Review
- DR5/WDR12 balances p65 stability promoting sunitinib resistance in renal cell carcinoma.Cell death and differentiation · 2026Article
- Targeting NXPH4/ALDH1L2 signaling suppresses enzalutamide resistance in prostate cancer.Cell death discovery · 2026Article
- The moonlighting functions of glycolytic enzymes in tumorigenesis.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer.Science advances · 2026Article
- Loss of UFL1 confers enzalutamide resistance of prostate tumors by regulating METTL16-mediated m6A modification of EEF1A1 mRNA.International journal of biological sciences · 2026Article
- Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysis.NPJ precision oncology · 2025Article
- Transcriptome Analysis Suggests PKD3 Regulates Proliferative Glucose Metabolism, Calcium Homeostasis and Microtubule Dynamics After MEF Spontaneous Immortalization.International journal of molecular sciences · 2025Article
- The role and therapeutic potential of glucose metabolism in multidrug resistance of cancer.Frontiers in cell and developmental biology · 2025Review
- Metabolic enzymes moonlighting to drive enzalutamide resistance in prostate cancer.Translational andrology and urology · 2024Article
- Transient TKI-resistant CD44+pBAD+ blasts undergo intrinsic homeostatic adaptation to promote the survival of acute myeloid leukemiaFrontiers in oncology · 2023Article
- Aberrant expression of multiple glycolytic enzyme genes is significantly associated with disease progression and survival outcomes in prostate cancers.American journal of clinical and experimental urology · 2023Article
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The next-generation androgen receptor (AR) inhibitor enzalutamide is the mainstay treatment for metastatic prostate cancer. Unfortunately, resistance occurs rapidly in most patients, and once resistance occurs, treatment options are limited. Therefore, there is an urgent need to identify effective targets to overcome enzalutamide resistance. Here, using a genome-wide CRISPR-Cas9 library screen, we found that targeting a glycolytic enzyme, phosphoglycerate mutase PGAM2, significantly enhanced the sensitivity of enzalutamide-resistant prostate cancer cells to enzalutamide both in vivo and in vitro. Inhibition of PGAM2 together with enzalutamide treatment triggered apoptosis by decreasing levels of the antiapoptotic protein BCL-xL and increasing activity of the proapoptotic protein BAD. Mechanistically, PGAM2 bound to 14-3-3ζ and promoted its interaction with phosphorylated BAD, resulting in activation of BCL-xL and subsequent resistance to enzalutamide-induced apoptosis. In addition, high PGAM2 expression, which is transcriptionally regulated by AR, was associated with shorter survival and rapid development of enzalutamide resistance in patients with prostate cancer. Together, these findings provide evidence of a nonmetabolic function of PGAM2 in promoting enzalutamide resistance and identify PGAM2 inhibition as a promising therapeutic strategy for enzalutamide-resistant prostate cancer. SIGNIFICANCE: PGAM2 promotes resistance to enzalutamide by activating antiapoptotic BCL-xL and suppressing apoptosis, indicating that PGAM2 is a potential target for overcoming enzalutamide resistance in prostate cancer.
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