AMPK as a Potential Anticancer Target - Friend or Foe?

Abstract

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 a 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.

Knockdown of ubiquitin associated protein 2-like inhibits the growth and migration of prostate cancer cells

“…8). Previous studies suggest that the AMPKα, Bad and PRAS40 signaling pathways are crucial for carcinoma cell proliferation and cell cycle control (10)(11)(12). Our data revealed that UBAP2L depletion induced proliferation inhibition and cell cycle arrest via the AMPKα, Bad and PRAS40 signaling pathways in prostate cancer.…”

“…AMPK regulates fatty acid metabolism, as well as modulates protein synthesis and cell growth. 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 a growth advantage (10). These findings underscore the complexity in the cellular function of AMPK in maintaining energy homeostasis under physiological versus pathological conditions.…”

AMPK Reverses the Mesenchymal Phenotype of Cancer Cells by Targeting the Akt–MDM2–Foxo3a Signaling Axis

“…However, it warrants attention that the role of AMPK as a metabolic sensor might vary in a cell type- or context-specific manner as emerging evidence suggests that tumor cells might also use AMPK activation as a survival strategy to undergo metabolic adaptation in the face of environmental stresses (30, 31), such as hypoxia (21), acidosis (22), and nutrient deprivation (21, 23). These dichotomous effects underscore differences in signaling networks downstream of AMPK in response to different stress signals.…”

Ser‐486/491 phosphorylation and inhibition of AMPKα activity is positively associated with Gleason score, metastasis, and castration‐resistance in prostate cancer: A retrospective clinical study

“…AMPK is a heterotrimeric protein consisting of a catalytic α subunit and two regulatory β and γ subunits; activation involves increased AMP/ADP binding to the γ subunit and subsequent Thr-183/172 phosphorylation of AMPKα1/α2 by upstream kinases serine/threonine kinase 11/liver kinase B1 (STK11/LKB1) or calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ) [1]. When active, AMPKα directly phosphorylates downstream metabolic and transcriptional targets, causing inhibition of cellular anabolism (for example, AMPKα phosphorylates acetyl-CoA carboxylase (ACC) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR), inhibiting fatty acid and cholesterol synthesis, respectively), increase in cellular catabolism, negative regulation of cell growth and proliferation by phosphorylation of the Raptor component of the mammalian target of rapamycin complex 1 (mTORC1) complex, and promotes autophagy [2]. …”