A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer

dc.contributor.authorMuralikrishnan, Vaishnavi
dc.contributor.authorFang, Fang
dc.contributor.authorGiven, Tyler C.
dc.contributor.authorPodicheti, Ram
dc.contributor.authorChtcherbinine, Mikhail
dc.contributor.authorMetcalfe, Tara X.
dc.contributor.authorSriramkumar, Shruthi
dc.contributor.authorO’Hagan, Heather M.
dc.contributor.authorHurley, Thomas D.
dc.contributor.authorNephew, Kenneth P.
dc.contributor.departmentMedical and Molecular Genetics, School of Medicineen_US
dc.date.accessioned2023-07-17T12:54:43Z
dc.date.available2023-07-17T12:54:43Z
dc.date.issued2022-07-15
dc.description.abstractOvarian cancer is a deadly disease attributed to late-stage detection as well as recurrence and the development of chemoresistance. Ovarian cancer stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors. Although chemotherapy may initially succeed at decreasing the size and number of tumors, it leaves behind residual malignant OCSCs. In this study, we demonstrate that aldehyde dehydrogenase 1A1 (ALDH1A1) is essential for the survival of OCSCs. We identified a first-in-class ALDH1A1 inhibitor, compound 974, and used 974 as a tool to decipher the mechanism of stemness regulation by ALDH1A1. The treatment of OCSCs with 974 significantly inhibited ALDH activity, the expression of stemness genes, and spheroid and colony formation. An in vivo limiting dilution assay demonstrated that 974 significantly inhibited CSC frequency. A transcriptomic sequencing of cells treated with 974 revealed a significant downregulation of genes related to stemness and chemoresistance as well as senescence and the senescence-associated secretory phenotype (SASP). We confirmed that 974 inhibited the senescence and stemness induced by platinum-based chemotherapy in functional assays. Overall, these data establish that ALDH1A1 is essential for OCSC survival and that ALDH1A1 inhibition suppresses chemotherapy-induced senescence and stemness. Targeting ALDH1A1 using small-molecule inhibitors in combination with chemotherapy therefore presents a promising strategy to prevent ovarian cancer recurrence and has the potential for clinical translation.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationMuralikrishnan V, Fang F, Given TC, et al. A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer. Cancers (Basel). 2022;14(14):3437. Published 2022 Jul 15. doi:10.3390/cancers14143437en_US
dc.identifier.urihttps://hdl.handle.net/1805/34402
dc.language.isoen_USen_US
dc.publisherMDPIen_US
dc.relation.isversionof10.3390/cancers14143437en_US
dc.relation.journalCancersen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0*
dc.sourcePMCen_US
dc.subjectALDH1A1en_US
dc.subjectCancer stem cellsen_US
dc.subjectChemotherapy resistanceen_US
dc.subjectOvarian canceren_US
dc.subjectSenescenceen_US
dc.titleA Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Canceren_US
dc.typeArticleen_US
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