Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells

M. J. Jung, J. K. Rho, Y. M. Kim, J. E. Jung, Y. B. Jin, Young-Gyu Ko, J. S. Lee, S. J. Lee, J. C. Lee, M. J. Park

Research output: Contribution to journalArticle

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Abstract

The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial-mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity in vitro and tumorigenicity in vivo. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance in vitro and exhibited stronger tumorigenic potential in vivo than CXCR4- cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.

Original languageEnglish
Pages (from-to)209-221
Number of pages13
JournalOncogene
Volume32
Issue number2
DOIs
Publication statusPublished - 2013 Jan 10

Fingerprint

Non-Small Cell Lung Carcinoma
Up-Regulation
Maintenance
Pharmaceutical Preparations
Neoplastic Stem Cells
Transfection
Lung Neoplasms
Phosphorylation
Pharmacology
A549 Cells
Epithelial-Mesenchymal Transition
Phosphatidylinositols
Small Interfering RNA
Phosphotransferases
Radiation
Cell Line
Therapeutics

Keywords

  • cancer stem cell
  • CXCR4
  • non-small cell lung cancer
  • PI3K/PTEN/Akt/mTOR signaling
  • STAT3 signaling
  • tumorigenicity

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells. / Jung, M. J.; Rho, J. K.; Kim, Y. M.; Jung, J. E.; Jin, Y. B.; Ko, Young-Gyu; Lee, J. S.; Lee, S. J.; Lee, J. C.; Park, M. J.

In: Oncogene, Vol. 32, No. 2, 10.01.2013, p. 209-221.

Research output: Contribution to journalArticle

Jung, MJ, Rho, JK, Kim, YM, Jung, JE, Jin, YB, Ko, Y-G, Lee, JS, Lee, SJ, Lee, JC & Park, MJ 2013, 'Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells', Oncogene, vol. 32, no. 2, pp. 209-221. https://doi.org/10.1038/onc.2012.37
Jung, M. J. ; Rho, J. K. ; Kim, Y. M. ; Jung, J. E. ; Jin, Y. B. ; Ko, Young-Gyu ; Lee, J. S. ; Lee, S. J. ; Lee, J. C. ; Park, M. J. / Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells. In: Oncogene. 2013 ; Vol. 32, No. 2. pp. 209-221.
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