Natural Steroidal Lactone Induces G1/S Phase Cell Cycle Arrest and Intrinsic Apoptotic Pathway by Up-Regulating Tumor Suppressive miRNA in Triple-Negative Breast Cancer Cells

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dc.contributor.authorShuaib, Mohd
dc.contributor.authorPrajapati, Kumari Sunita
dc.contributor.authorGupta, Sanjay
dc.contributor.authorKumar, Shashank
dc.date.accessioned2024-01-16T14:23:20Z
dc.date.accessioned2024-08-13T10:34:14Z
dc.date.available2024-01-16T14:23:20Z
dc.date.available2024-08-13T10:34:14Z
dc.date.issued2022-12-27T00:00:00
dc.description.abstractTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with minimal treatment options. In the present work, Withaferin A (WA), a natural steroidal lactone found in Withania somnifera (Solanaceae), was studied to deduce the miRNA expression modulation mediated anticancer mode of action in TNBC cells. Small RNA next generation sequencing (NGS) of WA (2 �M) and vehicle (0.1% DMSO)-treated MDA-MB-231 cells revealed a total of 413 differentially expressed miRNAs (DEMs) and demonstrated that WA potentially up-regulates the miR-181c-5p, miR-15a-5p, miR-500b-5p, miR-191-3p, and miR-34a-5p and down-regulates miR-1275, miR-326, miR-1908-5p, and miR-3940-3p among total DEMs. The NGS and qRT-PCR expression analysis revealed a significantly higher expression of miR-181c-5p among the top 10 DEMs. Predicted target genes of the DEMs showed enrichment in cancer-associated gene ontology terms and KEGG signaling pathways. Transient up-expression of mir-181c-5p showed a time-dependent decrease in MDA-MB-231 and MDA-MB-453 cell viability. Co-treatment of miR-181c-5p mimic and WA (at varying concentration) down-regulated cell cycle progression markers (CDK4 and Cyclin D1) at mRNA and protein levels. The treatment induced apoptosis in MDA-MB-231 cells by modulating the expression/activity of Bax, Bcl2, Caspase 3, Caspase 8, Caspase 3/7, and PARP at mRNA and protein levels. Confocal microscopy and Annexin PI assays revealed apoptotic induction in miRNA- and steroidal-lactone-treated MDA-MB-231 cells. Results indicate that the Withaferin A and miRNA mimic co-treatment strategy may be utilized as a newer therapeutic strategy to treat triple-negative breast cancer. � 2022 by the authors.en_US
dc.identifier.doi10.3390/metabo13010029
dc.identifier.issn22181989
dc.identifier.urihttps://doi.org/10.3390/metabo13010029
dc.identifier.urihttp://10.2.3.109/handle/32116/2907
dc.language.isoen_USen_US
dc.publisherMDPIen_US
dc.subjectanticanceren_US
dc.subjectapoptosisen_US
dc.subjectMiRNAen_US
dc.subjectphytochemicalen_US
dc.subjectsequencingen_US
dc.subjectWithania Aen_US
dc.titleNatural Steroidal Lactone Induces G1/S Phase Cell Cycle Arrest and Intrinsic Apoptotic Pathway by Up-Regulating Tumor Suppressive miRNA in Triple-Negative Breast Cancer Cellsen_US
dc.title.journalMetabolitesen_US
dc.typeArticleen_US
dc.type.accesstypeOpen Accessen_US

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