Exosomes Promote the Transition of Androgen-Dependent Prostate Cancer Cells into Androgen-Independent Manner Through Up-Regulating the Heme Oxygenase-1

Abstract

Yiming Zhang,1,2,* Binshen Chen,1,2,* Naijin Xu,3 Peng Xu,1,2 Wenfeng Lin,1– 3 Chunxiao Liu,1,2 Peng Huang1– 3 1Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Guangzhou Key Laboratory of Inflammatory and Immune Diseases, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan*These authors contributed equally to this workCorrespondence: Peng Huang; Chunxiao LiuDepartment of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]; [email protected]: Castration-resistant prostate cancer (CRPC) is still considered incurable, even though the mechanisms of CRPC had been extensively researched. Studies have demonstrated that exosomes in the tumor microenvironment contribute to prostate cancer development and progression. However, the role of exosomes in the process of CRPC progression has not yet been determined.Methods: Co-culturing and exosome treatment assays combined with in vitro and in vivo assays were performed to determine the function of exosomes in the transformation of androgen-dependent prostate cancer (ADPC) cells into androgen-independent cells. Then, the mRNA expression profiles of ADPC cells and ADPC cells co-cultured with androgen-independent prostate cancer (AIPC) cell-derived exosomes were studied using microarrays. After silencing the expression of heme oxygenase-1 (HMOX1), Western blotting, quantitative real-time PCR, immunohistochemistry (IHC) studies, and MTS assay were used to confirm the mechanisms of exosome participation in CRPC progression.Results: The results showed that ADPC cells acquired tolerance for androgen deprivation due to the exosome-mediated communication between cells. AIPC cell-derived exosomes promoted the transformation of ADPC cells into androgen-independent cells in vivo and in vitro. Microarray analysis revealed that HMOX1 in ADPC cells was up-regulated after treatment with AIPC cell-derived exosomes. Further results showed that HMOX1 is overexpressed in human AIPC specimens and protects ADPC cells from androgen deprivation.Conclusions: Our findings revealed that exosomes contribute to CRPC progression via promoting the transition of prostate cancer cells into an androgen-independent growth stage by activating HMOX1.Keywords: prostate cancer, castration resistance, exosomes, heme oxygenase-1

Keywords

• prostate cancer
• castration resistance
• exosomes
• heme oxygenase-1