AMPK as a metabolic tumor suppressor: control of metabolism and cell growth

Abstract

AMPK is an evolutionarily conserved fuel-sensing enzyme that is activated in shortage of energy and suppressed in its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia and hyperlipidemia, and inhibits proinflammatory changes. Thus, AMPK is a well-received therapeutic target for metabolic syndrome and Type 2 diabetes. Recent studies indicate that AMPK plays a role in linking metabolic syndrome and cancer. AMPK is an essential mediator of the tumor suppressor LKB1 and could be suppressed in cancer cells containing loss-of-function mutations of LKB1 or containing active mutations of B-Raf, or in cancers associated with metabolic syndrome. The activation of AMPK reprograms cellular metabolism and enforces metabolic checkpoints by acting on mTORC1, p53, fatty acid synthase and other molecules for regulating cell growth and metabolism. In keeping with in vitro studies, recent epidemiological studies indicate that the incidence of cancer is reduced in Type 2 diabetes treated with metformin, an AMPK activator. Thus, AMPK is emerging as an interesting metabolic tumor suppressor and a promising target for cancer prevention and therapy.

Figure 1. Essential Roles of LKB1/AMPK in controlling cell growth and tumorigenesis

LKB1/AMPK by regulating mTORC1, p53 and other important molecules control cellular processes, such as cell cycle checkpoint, apoptosis, autophagy and cell polarity. Dysregulation of LKB1/AMPK causes loss of these control points and thus leads to unrestrained growth. Only a few representative molecules that are directly relevant to growth control are listed here. TZD: Thiazolidinedione.

Figure 2. Interaction of AMPK with the ERK and PI3K pathways

Recent studies have demonstrated that the LKB1/AMPK axis functionally interacts with the mitogenic pathways: Atk could phosphorylate and inhibit AMPK; LKB1 is inhibited by oncogenic B-Raf in an ERK/RSK-dependent fashion; KSR associates with Raf/MEK, which is required for Raf/MEK activation. Recently, KSR2 has been shown to associate with AMPK and participate in its activation. It will be interesting to test if the KSR scaffolds, by tethering Raf/MEK and AMPK, play a role in determining cell growth or arrest; AMPK inhibits TORC1 by phosphorylating TSC2 and Raptor. This negative regulation is important, as TORC1 is a critical regulator for the growth of cancer cells bearing the loss-of-function mutations of PTEN or activating mutations of PI3K and Akt.

Figure 3. Suppression of AMPK results in loss of metabolic checkpoints

AMPK could be suppressed in metabolic syndrome and by activated Akt owing to mutation of PTEN or PI3K, or activated ERK/RSK due to Ras or B-Raf, leading to a loss of metabolic checkpoints. Likewise, increased insulin and IGF1 associated with metabolic syndrome can inhibit AMPK and stimulate cell proliferation, hyperplasia and malignant growth of cancer cells.

Figure 4. AMPK plays a role in reprogramming energy metabolism

AMPK activation could have two effects on energy metabolisms: acute effect, AMPK that is activated under metabolic stress, such as hypoxia, ischemia and glucose deprivation, stimulates fatty acid oxidation and, in some circumstances, such as in the heart, enhances glycolysis to generate more ATP; chronic effect, AMPK may inhibit glycolysis via its action on mTOR and p53. Thus, suppression of AMPK in some cancer might result in increased glycolysis, which may contribute to the Warburg effect.