Targeting CPT1B as a potential therapeutic strategy in castration‐resistant and enzalutamide‐resistant prostate cancer

Abstract

BackgroundProstate cancer is characterized by aberrant lipid metabolism, including elevated fatty acid oxidation. Carnitine palmitoyltransferase 1B (CPT1B) catalyzes the rate‐limiting step of fatty acid oxidation. This study aimed to determine if CPT1B has a critical role in prostate cancer progression and to identify its regulatory mechanism.MethodsCPT1B expression data from The Cancer Genome Atlas and Gene Expression Omnibus databases was compared with patient survival data. A tissue microarray was constructed with 60 samples of prostate cancer and immunohistochemically stained for CPT1B. Castration‐resistant prostate cancer (CRPC) cell lines 22RV1 and C4‐2 in which CPT1B expression had been stably knocked down were established; and cell proliferation, cell cycle distribution, and invasion were investigated by Cell Counting Kit‐8 (CCK‐8) and colony formation assays, flow cytometry, and Transwell assays, respectively. To examine the impact of androgen receptor (AR) inhibition on CPT1B expression, JASPAR CORE was searched to identify AR‐binding sites in CPT1B. Dual luciferase and ChIP assays were performed to confirm CPT1B activity and AR binding, respectively. Differentially expressed genes (DEGs) in prostate cancer underwent gene set enrichment analysis (GSEA). Enzalutamide‐resistant C4‐2 cells were generated and the mechanism of enzalutamide resistance and downstream signaling pathway changes of CPT1B to C4‐2 was explored through CCK‐8 test.ResultsCPT1B expression was upregulated in human prostate cancer compared with normal prostate tissue and was associated with poor disease‐free survival and overall survival. Silencing of CPT1B resulted in downregulated cell proliferation, reduced S‐phase distribution, and lower invasive ability, whereas the opposite was observed in CRPC cells overexpressing CPTB1. DEGS in prostate cancer were correlated with G‐protein–coupled receptor signaling, molecular transducer activity, and calcium ion binding. AR may regulate CPT1B expression and activity via specific binding sites, as confirmed by dual luciferase and ChIP assays. The CCK‐8 experiment demonstrated that CPT1B overexpression in C4‐2 cells did not significantly increase the ability of enzalutamide resistance. However, overexpression of CPT1B in C4‐2R cells significantly increased the enzalutamide resistance. Upregulation of CPT1B expression increased AKT expression and phosphorylation.ConclusionsCPT1B is upregulated in prostate cancer and is correlated with poor prognosis, indicating its potential as a biomarker. AR inhibits the transcription of CPT1B. In the CRPC cell line, overexpression of CPT1B alone cannot promote enzalutamide resistance, but in the drug‐resistant line C4‐2R, overexpression of CPT1B can promote the resistance of C4‐2R to enzalutamide.

SQLE Mediates Metabolic Reprogramming to Promote LN Metastasis in Castration-Resistant Prostate Cancer

“…27 Although the mechanism of androgen resistance is not fully clear, abnormal fatty acid metabolism has been shown to promote the resistance of CRPC cells to enzalutamide. 28 Overexpression of carnitine palmitoyltransferase 1B (CPT1B), a rate-limiting step of fatty acid oxidation, is reported to significantly increase enzalutamide resistance via increasing AKT expression and phosphorylation in CRPC cells. 28 This indicates that enhanced fatty acid oxidation could promote the drug resistance of CRPC cells.…”

“…28 Overexpression of carnitine palmitoyltransferase 1B (CPT1B), a rate-limiting step of fatty acid oxidation, is reported to significantly increase enzalutamide resistance via increasing AKT expression and phosphorylation in CRPC cells. 28 This indicates that enhanced fatty acid oxidation could promote the drug resistance of CRPC cells. Our study has found bicalutamide resistance induced SQLE highly expression refer to increased mitochondrial OXPHOS, which supplied energy source to maintain proliferation and metastasis in CPRC cells.…”

Analysis of Nuclear Encoded Mitochondrial Gene Networks in Cervical Cancer

“…Furthermore, targeting CPT1B in cancers with abnormal lipid metabolism and fatty acid oxidation (castration-resistant prostate cancer) is proposed. CPT1B overexpression is correlated with poor prognosis in prostate cancer (Abudurexiti et al, 2020). However, the role of CPT1B in CC is yet to be uncovered.…”

Identification of a Novel Lipid Metabolism-Related Gene Signature in Prognosis of Bladder Cancer

“…Carnitine palmitoyltransferase 1B (CPT1B) has been reported to be related with tumor proliferation and metastasis through regulating EMT in BLCA [34]. Overexpression of CPT1B was correlated with worse OS in prostate cancer [35]. Further study has revealed that AR-mediated CPT1B promoted castration-sensitive and castration-resistant prostate cancer (CRPC) progression by upregulating AKT expression and phosphorylation.…”