title: Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1.
abstract: Triple negative breast cancer (TNBC) is known to contain a high percentage of CD44(+) /CD24(-/low) cancer stem cells (CSCs), corresponding with a poor prognosis despite systemic chemotherapy. Chloroquine (CQ), an antimalarial drug, is a lysotropic reagent which inhibits autophagy. CQ was identified as a potential CSC inhibitor through in silico gene expression signature analysis of the CD44(+) /CD24(-/low) CSC population. Autophagy plays a critical role in adaptation to stress conditions in cancer cells, and is related with drug resistance and CSC maintenance. Thus, the objectives of this study were to examine the potential enhanced efficacy arising from addition of CQ to standard chemotherapy (paclitaxel) in TNBC and to identify the mechanism by which CQ eliminates CSCs in TNBCs. Herein, we report that CQ sensitizes TNBC cells to paclitaxel through inhibition of autophagy and reduces the CD44(+) /CD24(-/low) CSC population in both preclinical and clinical settings. Also, we are the first to report a mechanism by which CQ regulates the CSCs in TNBC through inhibition of the Janus-activated kinase 2 (Jak2)-signal transducer and activator of transcription 3 signaling pathway by reducing the expression of Jak2 and DNA methyltransferase 1.
authors.affiliation: Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Choi
authors.forename: Elvin
authors.initials: E
authors.lastname: Blanco
authors.forename: Yoo-Shin
authors.initials: YS
authors.lastname: Kim
authors.forename: Angel A
authors.initials: AA
authors.lastname: Rodriguez
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Tim Hui-Ming
authors.initials: TH
authors.lastname: Huang
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Guangxu
authors.initials: G
authors.lastname: Jin
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Landis
authors.forename: Lacey A
authors.initials: LA
authors.lastname: Burey
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Granados
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Dave
authors.forename: Helen H
authors.initials: HH
authors.lastname: Wong
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*
chemical_list: D002738:Chloroquine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Autophagy; Breast cancer stem cells; Chloroquine; DNMT1; Jak2