title: Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cells.
abstract: Adenosine monophosphate-activated protein kinase (AMPK) is a sensor for cellular energy status. When the cellular energy level is decreased, AMPK is activated and functions to suppress energy-consuming processes, including protein synthesis. Recently, AMPK has received attention as an attractive molecular target for cancer therapy. Several studies have revealed that the activation of AMPK by chemical stimulators, such as metformin, induces apoptosis in a variety of hematologic malignant cells. From another perspective, these results suggest that the function of AMPK is impaired in hematologic tumor cells. However, the precise mechanisms by which this impairment occurs are not well understood. In melanoma cells, oncogenic BRAF constitutively activates the extracellular signal-regulated kinase (ERK) pathway and phosphorylates liver kinase B1, an upstream activator of 5' adenosine monophosphate-activated protein kinase (AMPK), resulting in the inactivation of liver kinase B1 and AMPK. In this study, we analyzed whether ERK is involved in the suppression of AMPK activity using established and primary human leukemia cells. We found an inverse correlation between the intensity of ERK activity and the degree of AMPK activation after stimulation with either glucose deprivation or metformin. We also found that the inhibition of ERK activity by U0126 restored AMPK activation after metformin treatment. Furthermore, a combined treatment with metformin and U0126 enhanced the antileukemic activity of metformin. Importantly, metformin induced ERK activation by suppressing the protein levels of dual specificity phosphatase 6, a negative regulator of ERK. This crosstalk between AMPK and ERK could diminish the antileukemic activity of metformin. Taken together, our present observations suggest a novel therapeutic strategy for improving the efficacy of metformin in treating leukemia.
authors.affiliation: Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawashima
authors.affiliation: Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Mitsumori
authors.affiliation: Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shobu-Sueki
authors.affiliation: Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Department of Hematology and Oncology, University of Yamanashi, Yamanashi, Japan. Electronic address: kirito@yamanashi.ac.jp.
authors.forename: Keita
authors.initials: K
authors.lastname: Kirito
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000502:physiology*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D004347:Drug Interactions; D054642:Dual Specificity Phosphatase 6 / Q000502:physiology; D004789:Enzyme Activation; D025461:Feedback, Physiological; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000473:pathology*; D015479:Leukemia, Myelomonocytic, Acute / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008687:Metformin / Q000494:pharmacology; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D009363:Neoplasm Proteins; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C113580:U 0126; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; D005947:Glucose