Upregulation of ATP Binding Cassette Subfamily C Member 5 facilitates Prostate Cancer progression and Enzalutamide resistance via the CDK1-mediated AR Ser81 Phosphorylation Pathway

• Published in: International journal of biological sciences Vol. 17; no. 7; pp. 1613 - 1628
• Main Authors: Ji, Guangjie, He, Shiming, Huang, Cong, Gong, Yanqing, Li, Xuesong, Zhou, Liqun
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2021; Ivyspring International Publisher
• Subjects: Apoptosis; ATP; ATP-Binding Cassette Transporters - biosynthesis; ATP-Binding Cassette Transporters - genetics; Benzamides - pharmacology; Binding; Cancer therapies; Castration; CDC2 Protein Kinase - biosynthesis; CDC2 Protein Kinase - genetics; Cell Line, Tumor; Cell migration; Cell Proliferation; Chemotherapy; Cluster analysis; Drug resistance; Drug Resistance, Neoplasm; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Immunofluorescence; Immunohistochemistry; Male; Mass spectrometry; Metastasis; Nitriles - pharmacology; Phenylthiohydantoin - pharmacology; Phosphorylation; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Proteins; Research Paper; RNA, Neoplasm - genetics; Scientific imaging; Signal Transduction; Therapeutic targets; Transcription; Up-Regulation; Western blotting; United States > US; China; Castration-resistant prostate cancer; CDK1; AR; ABCC5; enzalutamide
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.59559

The treatment of advanced prostate cancer, castration-resistant prostate cancer, remains challenging. The mechanisms of action of ATP binding cassette subfamily C member 5 (ABCC5) in prostate cancer and its relationship with drug resistance are still unclear. Expression and prognostic analyses of ABCC5 were performed through bioinformatic methods and immunohistochemistry analyses in multiple public databases as well as in our own prostate cancer cohort. The biological function of ABCC5 in prostate cancer cells was evaluated by and cell proliferation and migration and invasion assays. The regulation of CDK1 by ABCC5 was determined via RT-qPCR, western blots, and immunofluorescence. ABCC5 was significantly overexpressed in prostate cancer and positively associated with unfavorable clinicopathological features and prognosis. Upregulation of ABCC5 could enhance the cell proliferation, migration, and invasion of prostate cancer and . Mechanistically, ABCC5 exerts a protumor effect by binding to and inhibiting the protein degradation of CDK1, which promotes the phosphorylation of AR at Ser81 by CDK1 and activates the transcriptional activity of AR on target genes. Moreover, the addition of a CDK1 inhibitor or knockdown of CDK1 significantly improved the efficacy of enzalutamide on prostate cancer cells. The ABCC5-CDK1-AR regulatory pathway could be a potential therapeutic target for advanced prostate cancer, especially castration-resistant prostate cancer (CRPC), to enhance the therapeutic effect of enzalutamide.