{"doi":"10.3390/cells12030405","title":"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.","journal":"Cells","year":2023,"id":339230,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1073271,"name":"Michael Chiaramonti","orcid":null,"position":1,"is_corresponding":false},{"id":871842,"name":"Ben Haddad","orcid":null,"position":2,"is_corresponding":false},{"id":871844,"name":"Robert Ranzenberger","orcid":null,"position":3,"is_corresponding":false},{"id":1073272,"name":"Heather Henning","orcid":null,"position":4,"is_corresponding":false},{"id":725087,"name":"Hind Al Khashali","orcid":null,"position":5,"is_corresponding":false},{"id":725086,"name":"Ravel Ray","orcid":null,"position":6,"is_corresponding":false},{"id":1073273,"name":"Ban Darweesh","orcid":null,"position":7,"is_corresponding":false},{"id":406411,"name":"Jeffrey Guthrie","orcid":"0009-0009-4329-7901","position":8,"is_corresponding":false},{"id":407943,"name":"Deborah Heyl","orcid":null,"position":9,"is_corresponding":false},{"id":406412,"name":"Hedeel Guy Evans","orcid":"0000-0002-7970-9084","position":10,"is_corresponding":false},{"id":725088,"name":"Kai-ling Coleman","orcid":null,"position":0,"is_corresponding":true}],"reference_count":117,"raw_metadata":null,"created_at":"2026-07-19T01:10:45.048445Z","pmid":"36766747","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}