The double-edged sword of AMPK signaling in cancer and its therapeutic implications

Abstract

5'-AMP-activated protein kinase (AMPK) plays a pivotal role in maintaining energy and redox homeostasis under various metabolic stress conditions. Metabolic adaptation, which can be triggered by the activation of AMPK during metabolic stress, is the critical process for cell survival through the maintenance of ATP and NADPH levels. The importance of such regulation of fundamental process poses the AMPK signaling pathway in one of the most attractive therapeutic targets in many pathologies such as diabetes and cancer. In cancer, however, accumulating data suggest that the role of AMPK would not be simply defined as anti- or pro-tumorigenic, but it seems to have two faces like a double-edged sword. Importantly, recent studies showed that the anti-tumorigenic effects of many 'indirect' AMPK activators such as anti-diabetic biguanides are not dependent on AMPK; rather the activation of AMPK induces the resistance to their cytotoxic effects, emphasizing the pro-tumorigenic effect of AMPK. In this review, we summarize and discuss recent findings suggesting the two faces of AMPK in cancer, and discuss how we can exploit this unique feature of AMPK for novel therapeutic intervention.

Fig. 1

The mechanisms of AMPK activation by various factors present in the tumor microenvironment. a The regulation of AMPK activity under normal conditions. b The mechanisms of AMPK activation by energy stress, matrix detachment and oxidative stress. c The mechanisms of AMPK activation by hypoxia. See text for details. Arrows denote activation, whereas horizontal bars indicate inhibition. PS protein synthesis, FAS fatty acid synthesis, FAO fatty acid oxidation, mtROS mitochondrial reactive oxygen species

Fig. 2

The hypotheses to explain the paradox of the LKB1-AMPK pathway and the CAMKK2-AMPK pathway in cancer. a The LKB1-AMPK pathway. Partial activity of AMPK in the absence of LKB1 may be sufficient to trigger metabolic adaptation, while insufficient to inhibit mTORC1 in the tumor microenvironment. b The LKB1-AMPK pathway. Additional mutations that could compensate for the loss of LKB1-induced metabolic adaptation may exist in LKB1-deficient cancer. c The CAMKK2-AMPK pathway. Unlike to LKB1 induced activation of AMPK, AR-CAMKK2 induced activation of AMPK can only activate metabolic adaptation signaling but not growth inhibitory signaling. See text for details. Arrows denote activation, whereas horizontal bars indicate inhibition

Fig. 3

Novel therapeutic strategies targeting AMPK and mitochondrial metabolism. a The dual effects of AMPK activation on tumorigenesis. b The effects of AMPK inhibitors such as sunitinib or midostaurine on anti- and pro-tumorigenic signaling of AMPK. c The effects of biguanides in combination with AMPK inhibitors on anti- and pro- tumorigenic signaling of AMPK. See text for details. Arrows denote activation, whereas horizontal bars indicate inhibition. Gray text indicates inactivation. REDD1 regulated in development and DNA damage responses 1, PRAS40 proline-rich Akt substrate of 40 kDa