Crosstalk Between AR and Wnt Signaling Promotes Castration-Resistant Prostate Cancer Growth

Jun Luo1 ,* Dan Wang2 ,* Xuechao Wan,2 Yangguang Xu,2 Yali Lu,2 Zhe Kong,2 Dujian Li,1 Wei Gu,1 Chenji Wang,2 Yao Li,2 Chaoneng Ji,2 Shaohua Gu,2 Yaoting Xu1 1Department of Urology, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaohua Gu; Yaoting Xu Email shaohuagu@fudan.edu.cn; ytxu64@vip.163.comIntroduction: Prostate cancer (PCa) is the most commonly diagnosed cancer and the third leading cause of cancer-related death in males in the United States. Despite the initial efficacy of androgen deprivation therapy in prostate cancer (PCa) patients, most patients progress to castration-resistant prostate cancer. However, the mechanisms underlying the androgen-independent progression of PCa remain largely unknown.Methods: In this study, we established a PCa cell line (LNCaP-AI) by maintaining LNCaP cells under androgen-depleted conditions. To explore the cellular and molecular mechanisms of androgen-independent growth of PCa, we analyzed the gene expression patterns in androgen-independent prostate cancer (AIPC) compared with that in androgen-dependent prostate cancer (ADPC). KEGG pathway analysis revealed that Wnt signaling pathways were activated after androgen deprivation therapy (ADT). In vitro experiments showed that the inhibition of Wnt pathway reduced AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis. Furthermore, WNT5A, LEF1 were identified as direct targets of AR by chromatin immunoprecipitation (ChIP) assay and public ChIP-seq datasets analysis.Results: In the present study, we found a regulatory mechanism through which crosstalk between androgen receptor (AR) and Wnt signals promoted androgen-independent conversion of PCa. The Wnt pathway was inhibited by androgen in androgen-dependent prostate cancer cells, but this blocking effect was not elicited in androgen-independent prostate cancer (AIPC) cells. Moreover, Wnt pathway genes WNT5A and LEF1 were directly downregulated by AR. In vitro experiments showed that inhibition of the Wnt pathways repressed AIPC cell growth by inhibiting cell cycle progression and promoting apoptosis. We found that WNT5A and LEF1 were downregulated in low-grade PCa but upregulated in metastatic PCa.Conclusion: In summary, we revealed that crosstalk between AR and Wnt signaling pathways promotes androgen-independent growth of PCa, which may provide novel therapeutic opportunities for castration-resistant prostate cancer.Keywords: Wnt pathway, prostate cancer, androgen receptor, androgen deprivation therapy