Prognostic significance of AMP-activated protein kinase expression and modifying effect of MAPK3 1 in colorectal cancer

• Published in: British journal of cancer Vol. 103; no. 7; pp. 1025 - 1033
• Main Authors: BABA, Y, NOSHO, K, OGINO, S, SHIMA, K, MEYERHARDT, J. A, CHAN, A. T, ENGELMAN, J. A, CANTLEY, L. C, LODA, M, GIOVANNUCCI, E, FUCHS, C. S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 28.09.2010
• Subjects: Aged; AMP-Activated Protein Kinases - metabolism; Biological and medical sciences; Biomarkers, Tumor - metabolism; Cancer research; Cell cycle; Cell growth; Class I Phosphatidylinositol 3-Kinases; Cohort analysis; Colorectal cancer; Colorectal Neoplasms - epidemiology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Cytotoxicity; DNA Methylation; Extracellular Signal-Regulated MAP Kinases - metabolism; Fatty acids; Female; Gastroenterology. Liver. Pancreas. Abdomen; Hospitals; Humans; Kinases; Male; Medical prognosis; Medical research; Medical schools; Medical sciences; Metabolism; Microsatellite Instability; Middle Aged; Molecular Diagnostics; Mutation; Nerve Tissue Proteins - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Prognosis; Proteins; Proto-Oncogene Proteins B-raf - genetics; RNA-Binding Proteins - metabolism; Roles; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; United States > US; Massachusetts; Rectal disease; Prognosis; Extracellular signal-regulated protein kinase; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Colorectal cancer; Mitogen-activated protein kinase; Malignant tumor; cAMP-dependent protein kinase; Colonic disease; Energy balance; Colon cancer; Cancerology; Digestive diseases; Intestinal disease; AMPK; Cancer; ERK
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605846

AMP-activated protein kinase (AMPK, PRKA) has central roles in cellular metabolic sensing and energy balance homeostasis, and interacts with various pathways (e.g., TP53 (p53), FASN, MTOR and MAPK3/1 (ERK)). AMP-activated protein kinase activation is cytotoxic to cancer cells, supporting AMPK as a tumour suppressor and a potential therapeutic target. However, no study has examined its prognostic role in colorectal cancers. Among 718 colon and rectal cancers, phosphorylated AMPK (p-AMPK) and p-MAPK3/1 expression was detected in 409 and 202 tumours, respectively, by immunohistochemistry. Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for clinical and tumoral features, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and KRAS, BRAF and PIK3CA mutations. Phosphorylated AMPK expression was not associated with survival among all patients. Notably, prognostic effect of p-AMPK significantly differed by p-MAPK3/1 status (P(interaction)=0.0017). Phosphorylated AMPK expression was associated with superior colorectal cancer-specific survival (adjusted HR 0.42; 95% confidence interval (CI), 0.24-0.74) among p-MAPK3/1-positive cases, but not among p-MAPK3/1-negative cases (adjusted HR 1.22; 95% CI: 0.85-1.75). Phosphorylated AMPK expression in colorectal cancer is associated with superior prognosis among p-MAPK3/1-positive cases, but not among p-MAPK3/1-negative cases, suggesting a possible interaction between the AMPK and MAPK pathways influencing tumour behaviour.