Janani Panneerselvam
IL-24 Inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis
Panneerselvam, Janani; Jin, Jiankang; Shanker, Manish; Lauderdale, Jason; Bates, Jonathan; Wang, Qi; Zhao, Yan D.; Archibald, Stephen J.; Hubin, Timothy J.; Ramesh, Rajagopal
Authors
Jiankang Jin
Manish Shanker
Jason Lauderdale
Jonathan Bates
Qi Wang
Yan D. Zhao
Professor Steve Archibald S.J.Archibald@hull.ac.uk
Professor in Molecular Imaging
Timothy J. Hubin
Rajagopal Ramesh
Abstract
© 2015 Panneerselvam et al. Background The stromal cell derived factor (SDF)-1/chemokine receptor (CXCR)-4 signaling pathway plays a key role in lung cancer metastasis and is molecular target for therapy. In the present study we investigated whether interleukin (IL)-24 can inhibit the SDF-1/CXCR4 axis and suppress lung cancer cell migration and invasion in vitro. Further, the efficacy of IL-24 in combination with CXCR4 antagonists was investigated. Methods Human H1299, A549, H460 and HCC827 lung cancer cell lines were used in the present study. The H1299 lung cancer cell line was stably transfected with doxycycline-inducible plasmid expression vector carrying the human IL-24 cDNA and used in the present study to determine the inhibitory effects of IL-24 on SDF-1/CXCR4 axis. H1299 and A549 cell lines w ere used in transient transfection studies. The inhibitory effects of IL-24 on SDF1/CXCR4 and its downstream targets were analyzed by quantitative RT-PCR, western blot, luciferase reporter assay, flow cytometry and immunocytochemistry. Functional studies included cell migration and invasion assays. Principal Findings Endogenous CXCR4 protein expression levels varied among the four human lung cancer cell lines. Doxycycline-induced IL-24 expression in the H1299-IL24 cell line resulted in reduced CXCR4 mRNA and protein expression. IL-24 post-transcriptionally regulated CXCR4 mRNA expression by decreasing the half-life of CXCR4 mRNA ( > 40%). Functional studies showed IL-24 inhibited tumor cell migration and invasion concomitant with reduction in CXCR4 and its downstream targets (pAKTS 473 , pmTORS 2448 , pPRAS40 T246 and HIF-1α). Additionally, IL-24 inhibited tumor cell migration both in the presence and absence of the CXCR4 agonist, SDF-1. Finally, IL-24 when combined with CXCR4 inhibitors (AMD3100, SJA5) or with CXCR4 siRNA demonstrated enhanced inhibitory activity on tumor cell migration. Conclusions IL-24 disrupts the SDF-1/CXCR4 signaling pathway and inhibits lung tumor cell migration and invasion. Additionally, IL-24, when combined with CXCR4 inhibitors exhibited enhanced anti-metastatic activity and is an attractive therapeutic strategy for lung metastasis
Citation
Panneerselvam, J., Jin, J., Shanker, M., Lauderdale, J., Bates, J., Wang, Q., Zhao, Y. D., Archibald, S. J., Hubin, T. J., & Ramesh, R. (2015). IL-24 Inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis. PLoS ONE, 10(3), Article e0122439. https://doi.org/10.1371/journal.pone.0122439
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 11, 2015 |
Online Publication Date | Mar 16, 2015 |
Publication Date | Mar 16, 2015 |
Deposit Date | Jan 20, 2020 |
Publicly Available Date | Mar 30, 2020 |
Journal | PLoS ONE |
Print ISSN | 1932-6203 |
Publisher | Public Library of Science |
Peer Reviewed | Peer Reviewed |
Volume | 10 |
Issue | 3 |
Article Number | e0122439 |
DOI | https://doi.org/10.1371/journal.pone.0122439 |
Keywords | Cell migration; Cancer treatment; Protein expression; Lung and intrathoracic tumors; Signal inhibition; Cancer cell migration; Metastasis; Small interfering RNAs |
Public URL | https://hull-repository.worktribe.com/output/518467 |
Publisher URL | https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122439#abstract0 |
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Copyright Statement
© 2015 Panneerselvam et al. This is an
open access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
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