Abstract
BackgroundThe 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.MethodsHuman 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 were 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 FindingsEndogenous 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 (pAKTS473, pmTORS2448, pPRAS40T246 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.ConclusionsIL-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.
Highlights
Effective treatment of lung cancer remains a challenge with an overall 5-year survival rate of patients diagnosed with lung cancer being less than 16% [1, 2]
Inhibition of CXCR4 was observed to occur starting at 4 h and the inhibitory activity was sustained to 24 h of testing (Fig. 1E)
Since CXCR4 has been shown to play a role in tumor metastasis by promoting cell migration and invasion we investigated whether the attenuation of CXCR4 expression by IL-24 had a consequential biological effect
Summary
Effective treatment of lung cancer remains a challenge with an overall 5-year survival rate of patients diagnosed with lung cancer being less than 16% [1, 2]. High cell surface expression of CXCR4 has been associated with metastatic activity of tumor cells [6, 7]. Consistent with the pre-clinical study results, clinical studies have shown high CXCR4 expression in NSCLC tumors is associated with metastasis and an increased risk of disease recurrence [9,10,11,12]. Molecular studies have shown that SDF-1/CXCR4 axis promotes tumor cell survival, cell migration and metastasis by modulating numerous signaling pathways [13, 14]. 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. The efficacy of IL-24 in combination with CXCR4 antagonists was investigated
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