AMP-activated protein kinase and human cancer: cancer metabolism revisited

Abstract

AMP-activated protein kinase (AMPK) and its upstream kinase, LKB1, act to both monitor and restore cellular energy in response to energy depletion. Studied extensively in liver and skeletal muscle, AMPK is phosphorylated and activated by LKB1 in response to increasing AMP/ATP ratios, which occur in a variety of settings including hypoxia, nutrient starvation and redox imbalance. Interest in the roles of both AMPK and LKB1 in cancer has grown substantially, following the identification of LKB1 as the tumor suppressor gene mutated in the Peutz-Jegher familial cancer syndrome. Patients with the Peutz-Jegher syndrome harbor a single inactive LKB1 gene, and acquisition of a second inactivating lesion (loss of heterozygosity) leads to the development of the cancer in a variety of organs. Thus, the loss of AMPK activation is hypothesized to promote the development of malignancy. Conversely, pharmacological AMPK activation has recently been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft and mouse cancer allografts. Previously, changes in cell metabolism that accompanied the malignant phenotype have largely been considered a consequence of cellular transformation. Now, AMPK and energy metabolism are linked to the development and maintenance of the malignant phenotype. These findings have led to renewed interest in AMPK and cancer cell metabolism in general as potential targets for cancer therapy.

The active form of the metabolic sensor AMP-activated protein kinase α (AMPKα) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis

“…[1][2][3][4][5][6][7][8] Although conceptually attractive, the ultimate molecular details through which the AMPK system may work as a "bioenergetics checkpoint" determining whether a cell can commit to a program of mitosis remains largely elusive. Jones et al elegantly demonstrated that the G 1 /S transition in mammalian cells is tethered to glucose availability by AMPK in a p53-dependent manner.…”

“…[1][2][3][4][5][6][7][8] In this scenario, AMPK interpreted microenvironmental bioenergetics may ensure a precise coordination between cellular to directly bind the mitotic apparatus to travel from centrosomes to the spindle midzone overlapping with essential mitotic and cytokinetic regulators at precise locations and specific times. This newly discovered link between the metabolic fuel gauge AMPK and the mitotic apparatus, once thought to lie in distinct signaling pathways, strongly suggests that AMPK may function as a putative cytokinetic tumor suppressor by physically tethering the bioenergetic state of a cell to the four-dimensional regulation of the chromosomal and cytoskeletal mitotic events.…”

“…[1][2][3][4] In this regard, we are beginning to accumulate substantial evidence indicating that the metabolic fuel gauge AMPK can also function as a canonical suppressor of cell proliferation: [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] (1) AMPK activation promotes the maintenance of a resting cell phenotype in mature tissues which do not require proliferation to keep its function; (2) an enhanced activity of AMPK further renders normal cells resistant to oncogenic transformation, and (3) Pharmacological hyperactivation of AMPK in cancer cells results in reduced cell growth both in vitro and in vivo. Not surprisingly, AMPK sits in-between bona fide tumor-suppressors in the complex signaling process that controls cell proliferation, namely the upstream activating AMPK Kinase LKB1 and the downstream AMPK effectors p53 and Tuberous sclerosis-2 (TSC2).…”

Endorepellin-evoked Autophagy Contributes to Angiostasis

“…Endorepellin Promotes Autophagy via AMPK␣ ActivationIt is well established that AMPK plays a key function in regulating autophagy and mTOR activity following phosphorylation of its catalytic ␣ subunit at Thr 172 (52,53). We hypothesized that endorepellin could induce autophagy through a canonical activation of AMPK␣.…”

Cancer Cell Metabolism

“…AMPK initiates suppression of the PI3K pathway by inhibiting both tuberous sclerosis 2 (TSC2) (Inoki et al 2003) and Raptor, a subunit of mTORC1 (Gwinn et al 2008). Consequently, AMPK blocks both protein translation and fatty acid (FA) synthesis Kuhajda 2008;Shackelford and Shaw 2009) and derepresses autophagy ) by inhibition of mTORC1. To generate energy under these conditions, the cell increases FA oxidation to generate acetyl-coenzyme A (CoA) as a substrate for the TCA cycle and oxidative phosphorylation .…”