Insulin Signalling-Inducible IFITM1 Promotes Multiple Myeloma Progression and Bortezomib Resistance.

Insulin substantially promotes the growth of malignant cells that overexpress the insulin receptor (INSR), and insulin excess has been recognised as a cancer-promoting factor in patients. Interferon-induced transmembrane protein 1 (IFITM1) is also overexpressed in various cancers. In this study, we investigate the association between insulin signalling-induced IFITM1 expression and multiple myeloma (MM) aggressiveness. We observed that expression of both INSR and IFITM1 was significantly elevated in symptomatic MM patients compared with those with monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM). Notably, IFITM1-but not INSR-expression correlated with prognosis following autologous stem cell transplantation and bortezomib-based induction therapy. Further analysis revealed that IFITM1 expression in bone marrow plasma cells was associated with the concentrations of insulin and insulin-like growth factor 2 (IGF-II) in the bone marrow microenvironment. Insulin and IGF-II enhanced MM cell proliferation through IFITM1 upregulation, whereas suppression of IFITM1 abrogated the proliferative effects of these ligands. Moreover, insulin and IGF-II attenuated apoptosis and the inhibition of cell migration induced by the proteasome inhibitors (PIs) bortezomib and carfilzomib, and these effects were reversed by IFITM1 knockdown. The ability of insulin to reduce bortezomib-induced apoptosis and G2/M phase cell cycle arrest was likewise dependent on IFITM1 expression. Collectively, these findings suggest that insulin-induced IFITM1 plays a pivotal role in MM progression and resistance to bortezomib, highlighting IFITM1 as a potential prognostic biomarker and therapeutic target.