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.

Genotoxic Damage Activates the AMPK-α1 Isoform in the Nucleus via Ca2+/CaMKK2 Signaling to Enhance Tumor Cell Survival

“…Although AMPK may indeed initially suppress the development of rapidly growing tumors and there may therefore be selection pressure for the LKB1-AMPK pathway to be downregulated (42), complete loss of function of AMPK in human cancers appears to be rare. In fact, there is increasing evidence that AMPK can under some circumstances enhance the growth of tumor cells, perhaps by protecting solid tumors against the environmental and nutritional stresses that occur before their new blood supply has been fully established (5,10,43,44). For example, a double knockout of a1 and a2 isoforms in immortalized MEFs prevented their growth as xenografts in immunodeficient mice (18).…”

Cysteine Modifications in the Pathogenesis of ALS

“…Other aspects of cysteine metabolism may be relevant in the pathogenesis of ALS, such as the direct oxidation of cysteines in proteins that are crucial for motor neuron metabolism and survival. One example is cysteines oxidation in AMP-activated protein kinase (AMPK) that is known to increase its activity (Zmijewski et al, 2010; Cardaci et al, 2012; Jeon and Hay, 2015). Intriguingly, an increased AMPK activity was reported in motor neuron cells expressing mutant SOD1 or TDP43 (Lim et al, 2012; Perera et al, 2014; Sui et al, 2014; Liu et al, 2015), in embryonic neural stem cells derived from SOD1 G93A mice (Perera et al, 2014) and in motor neurons of sALS and fALS patients (Liu et al, 2015).…”

mir-101-3p is a key regulator of tumor metabolism in triple negative breast cancer targeting AMPK

“…Under energy depletion, increased intracellular AMP directly binds to the regulatory γ-subunit and permits phosphorylation of the α-catalytic subunit at Thr172, thus activating AMPK. AMPK activation promotes energy generation processes, including glucose uptake, glycolysis, β-oxidation of fatty acids, etc, and inhibits energy consuming processes, such as protein or lipid synthesis [25, 26]. Recently, AMPK dysfunction has been highlighted in several malignancies [27], including breast cancer [28].…”