Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma

• Published in: Cell death & disease Vol. 12; no. 2; p. 206
• Main Authors: Dou, Renjie, Qian, Jinjun, Wu, Wei, Zhang, Yanxin, Yuan, Yuxia, Guo, Mengjie, Wei, Rongfang, Yang, Shu, Jurczyszyn, Artur, Janz, Siegfried, Beksac, Meral, Gu, Chunyan, Yang, Ye
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.02.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/109; 13/2; 13/21; 13/31; 14/28; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - genetics; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - metabolism; 38/39; 38/91; 5-alpha Reductase Inhibitors - pharmacology; 631/67/1990; 631/80/39; 64/60; 82/80; Adenine - analogs & derivatives; Adenine - pharmacology; AKT protein; Animals; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Bcl-2 protein; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell cycle; Cell Line, Tumor; Cell Proliferation; Dutasteride - pharmacology; Enzyme Repression; Female; Flow cytometry; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Immunofluorescence; Immunology; Life Sciences; Male; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Phagocytosis; Phosphatidylinositol 3-Kinase - metabolism; Prognosis; Proto-Oncogene Proteins c-akt - metabolism; Ribonucleic acid; RNA; Sex hormones; Signal Transduction; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcriptomics; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03510-4

Steroid 5α-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 (GEP) of sequential MM samples during the disease course, we found that the aberrant expression of SRD5A1 was correlated with progression and poor prognosis in MM patients. In this study, the oncogenic roles of SRD5A1 were validated in human MM cell lines (ARP1 and H929) and the xenograft MM model as well as the 5TMM mouse model. MTT and flow cytometry were used to assess MM cell proliferation, cell cycle, and apoptosis post inducible knockdown SRD5A1 by lentivirus-mediated short-hairpin RNA (shRNA). Transcriptomic sequencing, immunofluorescence, and western blot were used to investigate the effects of SRD5A1 suppression on cell apoptosis and autophagy. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family protein-mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. Meanwhile, the autophagy inhibitor (3-methyladenine) and SRD5A1 inhibitor (Dutasteride) were utilized to evaluate their anti-myeloma effect. Thus, our results demonstrated that SRD5A1 downregulation simultaneously regulated both the apoptosis and the autophagic process in MM cells. The dual autophagy–apoptosis regulatory SRD5A1 may serve as a biomarker and potential target for MM progression and prognosis.