Abstract
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.
Highlights
IntroductionAccording to statistics collected in China, the incidence of MM in 2016 was 1.60 per 100,000 person-years, with 1.84 per 100,000 person-years for males and 1.30 for females, respectively[1]
Multiple myeloma (MM) is the second most common hematologic malignancy worldwide
This study aimed to investigate the potential involvement of SRD5A1 during MM pathogenesis, and the evidence from in vivo and in vitro data demonstrated that SRD5A1-mediated MM cell autophagy via PI3K/Akt/ mTOR signaling pathway and induced MM cell apoptosis through B-cell lymphoma 2 (Bcl-2) proteins family in MM
Summary
According to statistics collected in China, the incidence of MM in 2016 was 1.60 per 100,000 person-years, with 1.84 per 100,000 person-years for males and 1.30 for females, respectively[1]. SRD5A1 was mainly expressed in the skin, scalp, liver, and brain tissues, while SRD5A2 was predominantly found in androgen target organs such as Official journal of the Cell Death Differentiation Association. Dou et al Cell Death and Disease (2021)12:206 the prostate and genital skin, but only SRD5A1 was upregulated in prostate cancers[7,8]. There is no report on the oncogenic role of SRD5A1 in MM progression, considering the unequal incidence rates between females and males of MM patients
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