Adenosine monophosphate-activated protein kinase (AMPK) is a key player in maintaining energy homeostasis in response to
metabolic stress. Beyond diabetes and metabolic syndrome, there is a growing interest in the therapeutic exploitation of the AMPK pathway
in cancer treatment in light of its unique ability to regulate cancer cell proliferation through the reprogramming of cell metabolism.
Although many studies support the tumor-suppressive role of AMPK, emerging evidence suggests that the metabolic checkpoint function
of AMPK might be overridden by stress or oncogenic signals so that tumor cells use AMPK activation as a survival strategy to gain
growth advantage. These findings underscore the complexity in the cellular function of AMPK in maintaining energy homeostasis under
physiological versus pathological conditions. Thus, this review aims to provide an overview of recent findings on the functional interplay
of AMPK with different cell metabolic and signaling effectors, particularly histone deacetylases, in mediating downstream tumor suppressive
or promoting mechanisms in different cell systems. Although AMPK activation inhibits tumor growth by targeting multiple signaling
pathways relevant to tumorigenesis, under certain cellular contexts or certain stages of tumor development, AMPK might act as a
protective response to metabolic stresses, such as nutrient deprivation, low oxygen, and low pH, or as downstream effectors of oncogenic
proteins, including androgen receptor, hypoxia-inducible factor-1α, c-Src, and MYC. Thus, investigations to define at which stage(s) of
tumorigenesis and cancer progression or for which genetic aberrations AMPK inhibition might represent a more relevant strategy than
AMPK activation for cancer treatment are clearly warranted.
Keywords: AMPK, metabolic homeostasis, cancer therapy, LKB1, mTORC1, HDAC, Foxo3a, HIF-1α.
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