DOI: 10.3390/cells12030405">
 

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

Document Type

Article

Publication Date

2023

Department/School

Chemistry

Publication Title

Cells

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.

Comments

J. Guthrie, D. Heyl, and H. G. Evans are faculty in EMU's Department of Chemistry.

*K.-L. Coleman, M. Chiaramonti, B. Haddad, R. Ranzenberger, H. Henning, H. Al Khashali, R. Ray, and B. Darweesh are EMU students.

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DOI: 10.3390/cells12030405

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