AMP-activated protein kinase and human cancer: cancer metabolism revisited.
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.
Kuhajda
F P
FP
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21201, USA. fkuhajda@jhmi.edu
D055372:AMP-Activated Protein Kinases; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000502:physiology
D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases