SWATH-MS reveals a key role for IPO7 in the molecular mechanism underlying antitumor effects of curcumin on Chronic Myelogenous Leukemia cells

Abstract

Imatinib represents the elective drug for the treatment of patients with Chronic Myelogenous Leukemia (CML). However, albeit it is effective in controlling CML and preventing progression to blast crisis (BC), it is not curative. Therefore, it is mandatory to find novel therapeutic combinations to completely eradicate CML. It was described that CML cells expressing higher level of BCR-ABL show an increased glucose metabolism (termed aerobic glycolysis or Warburg effect) correlated with a non-hypoxic induction of HIF-1α, factor implicated in leukemia stem cells (LSCs) maintenance[1,2]. In the present study, we demonstrated that curcumin, an Indian spice with multiple anticancer properties, is able to alter the HIF-1α cytoplasm/nucleus distribution in CML cells. As in vitro model we used the K562 cell line showing a constitutive non-hypoxic induction of HIF-1α. We observed that curcumin treatment of K562 impaired HIF-1α nuclear accumulation. SWATH-based quantitative proteomic analysis confirmed that curcumin induced a significant down-regulation of HIF-1α targets and the up-regulation of many structural and functional mitochondrial proteins. Moreover, among the proteins modulated by curcumin treatment, we found several importins and exportins. In particular, importin 7 (IPO7), described efficiently to accomplish nuclear import of HIF-1α[3], resulted downregulated in CML cells treated with curcumin. Interestingly, this protein is described as target of miRNA22 known as regulated by curcumin [4,5]. We demonstrated that in K562 cells curcumin induced the expression of miRNA22 causing the inhibition of IPO7 and the reduction of the nuclear import rate of HIF-1α. Finally, we show that curcumin treatment significantly sensitizes K562 cells to Imatinib.