Inhibition of AMP‐activated protein kinase sensitizes tumor cells to cisplatin‐induced apoptosis

Abstract

Platinum-containing drugs such as cisplatin are widely used in the treatment of various solid tumors. However, one of the major limitations to the use of these drugs is the acquisition of resistance to initially responsive tumors. Therefore, understanding the cellular responses to platinum-based drugs is critical for developing therapeutic approaches for increasing the effectiveness of cisplatin. In the present study, we investigated the effects of cisplatin on the activity of a cellular energy-sensing protein, AMP-activated protein kinase(AMPK). AMPK plays a major role in energy homeostasis by coordinating a number of adaptive responses under ATP-depleting conditions. Here we demonstrate that cisplatin rapidly activates AMPK in cancer cells. Moreover, inhibition of cisplatin-induced AMPK activity resulted in effective suppression of tumor growth as well as an increased sensitivity to cisplatin-induced apoptosis, and this effect was achieved via p53-dependent manner. We also attempted to characterize the relevant signal transduction pathway involving ATR and ERK. Furthermore, inhibition of AMPK in combination with cisplatin have a synergistic effect in decreasing growth of established human colon tumor xenografts. Overall, our data suggest that AMPK is a novel and critical regulatory component in adaptive response to cisplatin treatment, which further implies that a strategy combining AMPK inhibition with cisplatin could be developed as a novel therapeutic approach.