Proteome Changes Induced by Imatinib and Novel Imatinib Derivatives in K562 Human Chronic Myeloid Leukemia Cells

Abstract

Imatinib mesylate is the leading compound to treat chronic myeloid leukemia (CML) and other cancers, through its inhibition of Bcr-Abl tyrosine kinases. However, resistance to imatinib develops frequently, particularly in late-stage disease and has necessitated the development of new Bcr-Abl inhibitors. The synthesis of a new series of phenylaminopyrimidines, structurally related to imatinib, showed large interest since the introduction of nilotinib. Here, we compare the protein levels in K562 cells treated with either imatinib or with novel imatinib derivates. Our results revealed that among the 986 quantified proteins, 35 had significantly altered levels of expression by imatinib or its derivates. In a second series of experiments, we directly compared the proteomes of imatinib treated K562 cells with those K562 cells treated with any of the four imatinib derivates. More than 1029 protein were quantified, 80 of which had altered levels of expression. Both experiments pointed to changes in the expression of the ATP-dependent RNA helicase DDX3X and of two mitochondrial coiled-coil-helix-coiled-coil-helix domain-containing proteins.

Clinical biomarker discovery by SWATH-MS based label-free quantitative proteomics: impact of criteria for identification of differentiators and data normalization method

“…K562 harbours BCR/ABL oncogene which encodes a constitutively active tyrosine kinase, whose activity is inhibited by the small molecular inhibitor imatinib (IM). Inhibition of BCR/ABL activity by imatinib is known to cause quantitative changes in the proteome of K562 cells [13, 14].…”

DDX3X Multifunctionally Modulates Tumor Progression and Serves as a Prognostic Indicator to Predict Cancer Outcomes

“…DDX3X likely participates in imatinib-resistant chronic myeloid leukemia. Liquid chromatography -mass spectroscopy (LC-MS)/MS data indicate an increased protein level of DDX3X upon imatinib analog (SK23 and Y18) treatments designed to inhibit Bcr-Abl tyrosine kinases [55]. Lung cancer cells harboring EGFR exon 19 deletion and DDX3X cDNA have been observed to have reduced EGFR-tyrosine kinase inhibitor (TKI) sensitivity and cancer stem cell phenotypes, suggesting a role for DDX3X in drug resistance acquisition [56].…”

Targeting pro-tumorigenic signaling pathways in hematolymphoid malignancies

“…We analyzed DDX3X protein expression levels in a panel of 9 different cell lines derived from patients with various NHL subtypes -CTCL (HuT78, HH, MJ, MyLa), DLBCL (U2392), NKTCL (NKYS, SNK6), and BL (BJAB, Raji).In addition to the above 9 NHL cell lines, we included an acute T cell leukemia cell line Jurkat and a chronic myeloid leukemia cell line K562 line as controls since the expression of DDX3X protein has previously been shown in these two cell types (Arvaniti et al, 2014;Soto-Rifo and Ohlmann, 2013). Western immunoblot analysis showed variable levels of DDX3X expression in all the cell lines assessed in this study (…”