Abstract
The AMP-activated protein kinase (AMPK) is activated by energy stress and restores homeostasis by switching on catabolism, while switching off cell growth and proliferation. Findings that AMPK acts downstream of the tumor suppressor LKB1 have suggested that AMPK might also suppress tumorigenesis. In mouse models of B and T cell lymphoma in which genetic loss of AMPK occurred before tumor initiation, tumorigenesis was accelerated, confirming that AMPK has tumor-suppressor functions. However, when loss of AMPK in a T cell lymphoma model occurred after tumor initiation, or simultaneously with tumor initiation in a lung cancer model, the disease was ameliorated. Thus, once tumorigenesis has occurred, AMPK switches from tumor suppression to tumor promotion. Analysis of alterations in AMPK genes in human cancers suggests similar dichotomies, with some genes being frequently amplified while others are mutated. Overall, while AMPK-activating drugs might be effective in preventing cancer, in some cases AMPK inhibitors might be required to treat it.
Highlights
The AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis that is activated by increases in cellular AMP:ATP or ADP:ATP ratios (Carling 2017, Lin & Hardie 2017, Ross et al 2016b)
Given that the classical mechanism of AMPK activation by energy stress requires the tumorsuppressor kinase LKB1, and that AMPK switches off biosynthesis and the cell cycle, the idea began to emerge that AMPK may mediate many of the tumor-suppressor actions of LKB1 (Hardie & Alessi 2013)
Homozygous loss of Prkaa1 correlated with accelerated development of B cell lymphomas, with heterozygous loss having an intermediate effect. These results suggested that expression of Prkaa1 in the wild-type situation protected against B cell lymphoma, supporting the idea that AMPK can act as a tumor suppressor
Summary
The AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis that is activated by increases in cellular AMP:ATP or ADP:ATP ratios (Carling 2017, Lin & Hardie 2017, Ross et al 2016b). This occurs either when ATP synthesis is compromised (e.g., when cellular demand for oxygen or nutrients cannot be met by supply from blood vessels) or when ATP turnover is increased (e.g., during rapid cell proliferation).
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