Downregulation of Smad4 expression confers chemoresistance against imatinib mesylate to chronic myeloid leukemia K562 cells

Objective: Imatinib mesylate (IM), a tyrosine kinase inhibitor, exhibits clinically prominent effects against chronic myeloid leukemia (CML); however, a few patients have shown resistance to IM treatment, resulting in disease progression. SMAD4 is a tumor inhibitor that transduces TGF-β signaling and modulates genomic stability. Previous studies have indicated that decreased SMAD4 expression played a bidirectional role in chemosensitivity in many types of cancers. Therefore, this study aims to evaluate the association between IM sensitivity and decreased SMAD4 expression in human CML K562 cells.Methods: Bone marrow (BM) samples were acquired from the patients prior to treatment. qRT-PCR, Western Blotting (WB), colony formation assay (CFA), and Apoptosis assay were used to detect relevant indices.Results: SMAD4 expression was downregulated in the bone marrow and plasma of patients with multidrug-resistant CML as well as IM-resistant K562 (K562R) cells compared with samples collected from CML patients and K562 cells. SMAD4 overexpression inhibited IM-treated K562R cell proliferation and augmented Apoptosis, whereas SMAD4 silencing promoted viability and inhibited Apoptosis in IM-treated K562 cells. In addition, SMAD4 expression was inversely correlated with laminin subunit gamma 1 (LAMC1) expression. The upregulation or downregulation of LAMC1 expression partially abolished the effect of SMAD4 overexpression or silencing on the IM resistance of CML cells.Conclusion: The downregulation of SMAD4 expression might induce drug resistance in CML cells and displayed a possible mechanism through which SMAD4 modulates CML cell survival and Apoptosis upon IM treatment.