Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma. Cell Death Dis 2021 Feb 24;12(2):206
Date
02/26/2021Pubmed ID
33627630Pubmed Central ID
PMC7904855DOI
10.1038/s41419-021-03510-4Scopus ID
2-s2.0-85101499978 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
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.
Author List
Dou R, Qian J, Wu W, Zhang Y, Yuan Y, Guo M, Wei R, Yang S, Jurczyszyn A, Janz S, Beksac M, Gu C, Yang YAuthor
Siegfried Janz MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
3-Oxo-5-alpha-Steroid 4-Dehydrogenase5-alpha Reductase Inhibitors
Adenine
Animals
Antineoplastic Agents
Apoptosis
Autophagy
Cell Line, Tumor
Cell Proliferation
Dutasteride
Enzyme Repression
Female
Gene Expression Regulation, Neoplastic
Humans
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Multiple Myeloma
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
Signal Transduction
TOR Serine-Threonine Kinases
