Role of solute carrier transporters SLC25A17 and SLC27A6 in acquired resistance to enzalutamide in castration-resistant prostate cancer.

Prem P Kushwaha, Shiv S Verma, Eswar Shankar, Spencer Lin, Sanjay Gupta

Molecular carcinogenesis 2022 Apr

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Enzalutamide (XTANDI®), an antiandrogen, is used for the treatment of advanced-stage prostate cancer. Approximately, 60% of patients receiving enzalutamide show initial remission followed by disease relapse with the emergence of highly aggressive castration-resistant prostate cancer. Solute carrier (SLC) proteins play a critical role in the development of drug resistance by altering cellular metabolism. Transcriptome analysis revealed the predominance of SLC25A17 and SLC27A6 in enzalutamide-resistant prostate cancer cells; however, their role in antiandrogen resistance has not been elucidated. sgRNA-mediated knockdown of SLC25A17 and SLC27A6 suppressed cell proliferation and migration in enzalutamide-resistant cells. An induction of G1/S cell cycle arrest and abundance of hypo-diploid cells along with the reduction in the protein expression CyclinD1 and CDK6, the checkpoint factors, was observed including increased cell death as evident by BAX upregulation in knockdown cells. Inhibition of SLC25A17 and SLC27A6 resulted in downregulation of fatty acid synthase and acetyl-CoA carboxylase with parallel decrease in the levels of lactic acid in enzalutamide resistant cells. However, downregulation of triglyceride and citric acid was only observed in SLC25A17 silenced cells. The protein-protein interaction of SLC25A17 and SLC27A6 revealed alteration in some common drug-resistant and metabolism-related genes. Analysis of The Cancer Genome Atlas database exhibiting high SLC25A17 and SLC27A6 gene expression in prostate cancer patients were associated with poor survival than those with low expression of these proteins. In conclusion, SLC25A17 and SLC27A6 and its interactive network play an essential role in the development of enzalutamide resistance through metabolic reprogramming and may be identified as therapeutic target(s) to circumvent drug resistance. © 2021 Wiley Periodicals LLC.

Citation

Prem P Kushwaha, Shiv S Verma, Eswar Shankar, Spencer Lin, Sanjay Gupta. Role of solute carrier transporters SLC25A17 and SLC27A6 in acquired resistance to enzalutamide in castration-resistant prostate cancer. Molecular carcinogenesis. 2022 Apr;61(4):397-407