GAD1 contributes to the progression and drug resistance in castration resistant prostate cancer

Cancer Cell International

Research

Ruiji Liu¹  Yifan Liu²  Weipu Mao³  Lilin Wan⁴ 

[1] Department of Urology, Affiliated Zhongda Hospital of Southeast University, 87 Dingjia Bridge Hunan Road, 210009, Nanjing, China;Department of Urology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China;Department of Urology, Affiliated Zhongda Hospital of Southeast University, 87 Dingjia Bridge Hunan Road, 210009, Nanjing, China;Southeast University, 87 Dingjia Bridge Hunan Road, 210009, Nanjing, China;Department of Urology, People’s Hospital of Putuo District, 200000, Shanghai, China;Department of Urology, Affiliated Zhongda Hospital of Southeast University, 87 Dingjia Bridge Hunan Road, 210009, Nanjing, China;Department of Urology, People’s Hospital of Putuo District, 200000, Shanghai, China;Department of Urology, Affiliated Zhongda Hospital of Southeast University, 87 Dingjia Bridge Hunan Road, 210009, Nanjing, China;Southeast University, 87 Dingjia Bridge Hunan Road, 210009, Nanjing, China;

关键词: GAD1;    Prostate cancer;    Castration resistant;    Drug resistance;    Immune;   

DOI  :  10.1186/s12935-023-03093-4

 received in 2023-02-06, accepted in 2023-10-06,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundProstate cancer is currently the second most lethal malignancy in men worldwide due to metastasis and invasion in advanced stages. Studies have revealed that androgen deprivation therapy can induce stable remission in patients with advanced prostate cancer, although most patients will develop castration-resistant prostate cancer (CRPC) in 1–2 years. Docetaxel and enzalutamide improve survival in patients with CRPC, although only for a short time, eventually patients develop primary or secondary resistance, causing disease progression or biochemical relapse.MethodsThe gene expression profiles of docetaxel-sensitive or -resistant prostate cancer cell lines, namely GSE33455, GSE36135, GSE78201, GSE104935, and GSE143408, were sequentially analyzed for differentially expressed genes and progress-free interval significance. Subsequently, the overall survival significance and clinic-pathological features were analyzed by the R package. The implications of hub genes mutations, methylation in prostate cancer and the relationship with the tumor immune cell infiltration microenvironment were assessed with the help of cBioPortal, UALCAN and TISIDB web resources. Finally, effects of the hub genes on the progression and drug resistance in prostate cancer were explored using reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, cell phenotype, and drug sensitivity.ResultGlutamate decarboxylase 1 (GAD1) was tentatively identified by bioinformatic analysis as an hub gene for the development of drug resistance, including docetaxel and enzalutamide, in prostate cancer. Additionally, GAD1 expression, mutation and methylation were significantly correlated with the clinicopathological features and the tumor immune microenvironment. RT-PCR, immunohistochemistry, cell phenotype and drug sensitivity experiments further demonstrated that GAD1 promoted prostate cancer progression and decreased the therapeutic effect of docetaxel or enzalutamide.ConclusionThis research confirmed that GAD1 was a hub gene in the progression and development of drug resistance in prostate cancer. This helped to explain prostate cancer drug resistance and provides new immune-related therapeutic targets and biomarkers for it.

【 授权许可】

CC BY   
© The Author(s) 2023

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