Abstract 1713: IL-24 inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis

Abstract

Abstract Introduction The stromal cell derived factor (SDF)-1/chemokine receptor (CXCR)-4 signaling pathway plays a key role in lung cancer metastasis. Therefore, disrupting the SDF-1/CXCR4 signaling axis will reduce the incidence of lung metastasis. 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 lung tumor cell line was stably transfected with a tetracycline-inducible plasmid vector carrying the IL-24. Upon addition of doxycycline (Dox; 1μg/ml), cells were induced to express IL-24 protein. The expression levels of CXCR4 and its downstream molecular mechanisms in H1299 cells were analyzed. The inhibitory effect of IL-24 on SDF-1/CXCR4 axis is determined by RT-qPCR, western blot, luciferase reporter assay, flow-cytometry and immuno-cytochemistry and the consequence of its inhibition on cell migration, and invasion. Results Endogenous CXCR4 protein expression levels varied among four human lung cancer cell lines with H1299 cells showing the highest expression. Doxycycline-induced IL-24 expression in the H1299-IL-24 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%). Associated with CXCR4 inhibition was the reduced protein expression of pAKTS473, pmTORS2448, pPRAS40T246 and HIF-1α. IL-24 inhibited tumor cell migration and invasion both in the presence and absence of the CXCR4 agonist, SDF-1. However, the combinatorial effect of either IL-24 combined with CXCR4 inhibitors (AMD3100, SJA5) or with CXCR4 siRNA demonstrated enhanced inhibitory activity on tumor cell migration. Conclusions Our study results demonstrate that IL-24 inhibits lung tumor cell migration and invasion by disrupting the SDF-1/CXCR4 signaling pathway and exhibits enhanced anti-metastatic activity when combined with CXCR4 inhibitors. Citation Format: Janani Panneerselvam, Jiankang Jin, Manish Shanker, Jason Lauderdale, Jonathan Bates, Qi Wang, Daniel Zhao, Stephen Archibald, Timothy Hubin, Rajagopal Ramesh. IL-24 inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1713. doi:10.1158/1538-7445.AM2015-1713