Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells
- Authors
- Jung, M-J; Rho, J-K; Kim, Y-M; Jung, J. E.; Jin, Y. B.; Ko, Y-G; Lee, J-S; Lee, S-J; Lee, J. C.; Park, M-J
- Issue Date
- Jan-2013
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- non-small cell lung cancer; cancer stern cell; CXCR4; PI3K/PTEN/Akt/mTOR signaling; STAT3 signaling; tumorigenicity
- Citation
- ONCOGENE, v.32, no.2, pp.209 - 221
- Indexed
- SCIE
SCOPUS
- Journal Title
- ONCOGENE
- Volume
- 32
- Number
- 2
- Start Page
- 209
- End Page
- 221
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/26807
- DOI
- 10.1038/onc.2012.37
- ISSN
- 0950-9232
- 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-1 alpha 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 sternness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC. Oncogene (2013) 32, 209-221; doi:10.1038/onc.2012.37; published online 27 February 2012
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