Knock-down of CIAPIN1 sensitizes K562 chronic myeloid leukemia cells to Imatinib by regulation of cell cycle and apoptosis-associated members via NF-κB and ERK5 signaling pathway

Abstract

CIAPIN1 (cytokine-induced apoptosis inhibitor 1) was recently identified as an essential downstream effector of the Ras signaling pathway. However, its potential role in regulating myeloid leukemia cells sensitivity to Imatinib remains unclear. In this study, we found depletion of CIAPIN1 inhibited proliferation and triggered more apoptosis of K562CML (chronic myeloid leukemia) cells with or without Imatinib treatment. Meanwhile, CIAPIN1 depletion decreased ERK5 phosphorylation and NF-κB activity. Importantly, treating CIAPIN1-depleted K562 cells with ERK5 signaling pathway specific inhibitor, XMD8-92, further inhibited proliferation and promoted apoptosis with or without Imatinib treatment. Treatment with the NF-κB specific inhibitor, Bay 11-7082, induced nearly the same inhibition of proliferation and promotion of apoptosis conferred by CIAPIN1 depletion as was observed with XMD8-92 treatment. Further, XMD8-92 and Bay 11-7082 synergistically inhibited proliferation and promoted apoptosis of CIAPIN1-depleted K562 cells with or without Imatinib treatment. The nude mice transplantation model was also performed to confirm the enhanced sensitivity of CIAPIN1-depleted K562 cells to Imatinib. Thus, our results provided a potential management by which CIAPIN1 knock-down might have a crucial impact on enhancing sensitivity of K562 cells to Imatinib in the therapeutic approaches, indicating that CIAPIN1 knock-down might serve as a combination with chemotherapeutical agents in leukemia diseases therapy.

Keywords: CIAPIN1; ERK5; Imatinib; K562 cells; NF-κB.