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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/45010
Title: Reactive oxygen species mediate cancer stem-like cells and determine bortezomib sensitivity via Mcl-1 and Zeb-1 in mantle cell lymphoma
Authors: Sudjit Luanpitpong
Jirarat Poohadsuan
Parinya Samart
Chayanin Kiratipaiboon
Yon Rojanasakul
Surapol Issaragrisil
West Virginia University
Faculty of Medicine, Siriraj Hospital, Mahidol University
Wattanosoth Hospital
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Nov-2018
Citation: Biochimica et Biophysica Acta - Molecular Basis of Disease. Vol.1864, No.11 (2018), 3739-3753
Abstract: © 2018 Elsevier B.V. Mantle cell lymphoma (MCL) is an aggressive, incurable non-Hodgkin B-cell lymphoma with good initial response to therapy then subsequently relapse. Cancer stem cells (CSCs) are considered to be an underlying cause of these inevitable drug resistance and tumor regrowth, but how CSCs are regulated is largely unknown. We demonstrate here for the first time the existence of CSC-like subpopulations that are modulated by reactive oxygen species (ROS) in MCL cell lines and patient-derived primary cells in an inverse correlation with bortezomib (BTZ) sensitivity. Using various known donors and inhibitors of cellular superoxide (O 2 [rad] − ), hydrogen peroxide (H 2 O 2 ) and hydroxyl radical ([rad]OH), we unveil their distinct roles in the regulation of CSC-like subpopulations and thus MCL response to BTZ. O 2 [rad] − inhibits CSC-like cells and sensitizes BTZ-induced apoptosis, whereas H 2 O 2 conversely enriches CSC-like cells and protects against apoptosis and [rad]OH has minimal effects. We further observed that an anti-apoptotic Mcl-1 and a transcription factor Zeb-1 are favorable targets of O 2 [rad] − and H 2 O 2 , respectively. Using small molecule inhibition, ectopic expression and CRISPR/Cas9-mediated gene manipulation, we verified the roles of Mcl-1 and Zeb-1 in CSC and apoptosis regulation by O 2 [rad] − and H 2 O 2 . Our findings provide a novel mechanistic insight into the significance of redox status of MCL cells in determining their drug response via CSC-like subpopulations, which are imperative to a better understanding of therapeutic resistance and relapse.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85053429721&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/45010
ISSN: 1879260X
09254439
Appears in Collections:Scopus 2018

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