Phosphorylation of IGFBP-3 by Casein Kinase 2 Blocks Its Interaction with Hyaluronan, Enabling HA-CD44 Signaling Leading to Increased NSCLC Cell Survival and Cisplatin Resistance

Abstract

Cisplatin is a platinum agent used in the treatment of non-small cell lung cancer (NSCLC). Much remains unknown regarding the basic operative mechanisms underlying cisplatin resistance in NSCLC. In this study, we found that phosphorylation of IGFBP-3 by CK2 (P-IGFBP-3) decreased its binding to hyaluronan (HA) but not to IGF-1 and rendered the protein less effective at reducing cell viability or increasing apoptosis than the non-phosphorylated protein with or without cisplatin in the human NSCLC cell lines, A549 and H1299. Our data suggest that blocking CD44 signaling augmented the effects of cisplatin and that IGFBP-3 was more effective at inhibiting HA-CD44 signaling than P-IGFBP-3. Blocking CK2 activity and HA-CD44 signaling increased cisplatin sensitivity and more effectively blocked the PI3K and AKT activities and the phospho/total NFκB ratio and led to increased p53 activation in A549 cells. Increased cell sensitivity to cisplatin was observed upon co-treatment with inhibitors targeted against PI3K, AKT, and NFκB while blocking p53 activity decreased A549 cell sensitivity to cisplatin. Our findings shed light on a novel mechanism employed by CK2 in phosphorylating IGFBP-3 and increasing cisplatin resistance in NSCLC. Blocking phosphorylation of IGFBP-3 by CK2 may be an effective strategy to increase NSCLC sensitivity to cisplatin.