Work

IGFBP5 negatively regulates adhesion-mediated bortezomib resistance and modulates FAK/Src signaling in multiple myeloma

Year: 2026

Type: article

Abstract: Multiple myeloma (MM) is the second most common hematologic malignancy, and drug resistance in relapsed/refractory disease remains a major therapeutic challenge. The role of insulin-like growth factor binding protein 5 (IGFBP5) in MM progression and microenvironment-associated drug resistance remains incompletely understood. We integrated public gene-expression datasets (GSE6477, GSE31161, GSE136400, and GSE4204) with analyses of primary bone marrow samples. IGFBP5 overexpression and knockdown approaches were used to assess myeloma cell adhesion, BTZ response, and FAK/Src phosphorylation. IGFBP5 promoter methylation was evaluated using NGS-based bisulfite sequencing. IGFBP5 expression was reduced in MM and further decreased at relapse, with lower expression associated with adverse clinical features and poorer survival. Relapsed samples exhibited increased IGFBP5 promoter methylation, whereas demethylation treatment restored its expression. IGFBP5 overexpression reduced myeloma cell adhesion to fibronectin (FN) and HS-5 stromal cells and attenuated adhesion-mediated bortezomib (BTZ) resistance. Conversely, IGFBP5 knockdown enhanced cell adhesion and increased BTZ-treated cell viability under adhesive, but not suspension, conditions. IGFBP5 overexpression and knockdown were associated with decreased and increased FAK/Src phosphorylation, respectively. IGFBP5 overexpression also attenuated IGF-1-induced ITGB7 expression, while co-immunoprecipitation suggested an association between IGFBP5 and an IGF-1-containing protein complex. Complementary overexpression and knockdown findings support IGFBP5 as a negative regulator of adhesion-associated BTZ resistance in MM, potentially involving IGF-1-associated ITGB7 expression and FAK/Src signaling. These findings identify IGFBP5 as a candidate molecular target for further investigation into microenvironment-associated drug resistance in multiple myeloma.

Source: Clinical and Experimental Medicine

DOI: 10.1007/s10238-026-02383-1

Authors: Yue Peng, Jie Yan, Yifan Zuo, Xiaoqing Dong, Bing Chen

Institutions: Nanjing Drum Tower Hospital, Nanjing University

Language: English

Topic: Multiple Myeloma Research and Treatments

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,790