Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1

Dong Soon Choi, Elvin Blanco, Yoo Shin Kim, Angel A. Rodriguez, Hong Zhao, Hui-ming Huang, Chun-liang Chen, Guangxu Jin, Melissa D. Landis, Lacey A. Burey, Wei Qian, Sergio M. Granados, Bhuvanesh Dave, Helen H. Wong, Mauro Ferrari, Stephen T C Wong, Jenny C. Chang

Research output: Contribution to journalArticle

42 Citations (Scopus)

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. Stem Cells 2014;32:2309-2323

Original languageEnglish (US)
Pages (from-to)2309-2323
Number of pages15
JournalStem Cells
Volume32
Issue number9
DOIs
StatePublished - 2014

Fingerprint

Janus Kinase 2
Neoplastic Stem Cells
Chloroquine
Triple Negative Breast Neoplasms
Autophagy
Paclitaxel
Drug Therapy
STAT3 Transcription Factor
Antimalarials
Methyltransferases
Transcriptome
Drug Resistance
Computer Simulation
Population
Stem Cells
Maintenance
DNA

Keywords

  • Autophagy
  • Breast cancer stem cells
  • Chloroquine
  • DNMT1
  • Jak2

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Choi, D. S., Blanco, E., Kim, Y. S., Rodriguez, A. A., Zhao, H., Huang, H., ... Chang, J. C. (2014). Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells, 32(9), 2309-2323. https://doi.org/10.1002/stem.1746

Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. / Choi, Dong Soon; Blanco, Elvin; Kim, Yoo Shin; Rodriguez, Angel A.; Zhao, Hong; Huang, Hui-ming; Chen, Chun-liang; Jin, Guangxu; Landis, Melissa D.; Burey, Lacey A.; Qian, Wei; Granados, Sergio M.; Dave, Bhuvanesh; Wong, Helen H.; Ferrari, Mauro; Wong, Stephen T C; Chang, Jenny C.

In: Stem Cells, Vol. 32, No. 9, 2014, p. 2309-2323.

Research output: Contribution to journalArticle

Choi, DS, Blanco, E, Kim, YS, Rodriguez, AA, Zhao, H, Huang, H, Chen, C, Jin, G, Landis, MD, Burey, LA, Qian, W, Granados, SM, Dave, B, Wong, HH, Ferrari, M, Wong, STC & Chang, JC 2014, 'Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1', Stem Cells, vol. 32, no. 9, pp. 2309-2323. https://doi.org/10.1002/stem.1746
Choi, Dong Soon ; Blanco, Elvin ; Kim, Yoo Shin ; Rodriguez, Angel A. ; Zhao, Hong ; Huang, Hui-ming ; Chen, Chun-liang ; Jin, Guangxu ; Landis, Melissa D. ; Burey, Lacey A. ; Qian, Wei ; Granados, Sergio M. ; Dave, Bhuvanesh ; Wong, Helen H. ; Ferrari, Mauro ; Wong, Stephen T C ; Chang, Jenny C. / Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. In: Stem Cells. 2014 ; Vol. 32, No. 9. pp. 2309-2323.
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