Down-regulation of SRD5A1 induces autophagy and apoptosis in multiple myeloma

Steroid 5a-reductase type I (SRD5A1) is a validated oncogene in many sex hormone-related cancers, but its role in multiple myeloma (MM) remains unknown. Based on gene expression profiling of sequential MM samples during disease course, we found that high SRD5A1 expression was correlated with progression and poor prognosis in MM patients. In this study, we assessed the SRD5A1 function in promoting MM cell growth, cell cycle and tumorigenesis by using different human MM cell lines, the xenograft mouse and 5TMM mouse models. Applying lentivirus-mediated short-hairpin RNA (shRNA) method, inducible knockdown of SRD5A1 inhibited myeloma cell growth and induced cell apoptosis as well as autophagy. Meanwhile, the SRD5A1 knockdown-induced apoptosis was aggravated by the autophagy inhibitor 3-methyladenine. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family proteins mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. We also evaluated the therapeutic effect of SRD5A1 inhibitor, Dutasteride, on improving the survival rate of MM mouse model. To summarize, our findings demonstrate that SRD5A1 may serve as a biomarker for MM progression and prognosis, indicating that the dual autophagy-apoptosis regulatory SRD5A1 is a potential target for future therapies in MM patients. Overall design: Transcriptomic RNA-Seq to profile differentially expressed mRNAs in ARP1 cells when SRD5A1 gene was knocked donw by a (Dox)-inducible lentivirus-mediated shRNA (AK_SRD5A1 vs AKdox_SRD5A1).