Differential crosstalk between the AMPK and PI3K/Akt pathways in breast cancer cells of differing genotypes: Leptin inhibits the effectiveness of AMPK activation.
AMP-activated protein kinase (AMPK), a sensor of cellular energy, is widely reported as a potential therapeutic target in treatment of breast and other cancers. The activated enzyme has been shown to be a promising anti-proliferative agent in breast cancer cell lines. However, little data exist on crosstalk between AMPK and the cellular survival axis of PI3K/Akt/mTOR pathway and the impact of microenvironment on cellular responses to AMPK activation. We present results which show differential crosstalk between AMPK and Akt, dependent on the cellular genetics of each breast cancer cell type. We also show that leptin blocks activation of AMPK and partially or completely attenuates the anti-proliferative effect of AMPK activation depending on the cell type. This suggests that leptin within the local environment might impose limitations on therapeutic usage of AMPK activators in cancer, thereby attenuating their effective use in many obese subjects.
Department of Human Metabolism, The Medical School, University of Sheffield, Sheffield, S10 2RX, UK.
Omar S
OS
El-Masry
Department of Human Metabolism, The Medical School, University of Sheffield, Sheffield, S10 2RX, UK.
Kaltoom
K
Al-Sakkaf
Department of Human Metabolism, The Medical School, University of Sheffield, Sheffield, S10 2RX, UK.
Barry L
BL
Brown
Department of Human Metabolism, The Medical School, University of Sheffield, Sheffield, S10 2RX, UK.
Pauline R M
PR
Dobson
D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D020738:Leptin / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics
D055372:AMP-Activated Protein Kinases; D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human