TY - JOUR
T1 - Prognostic significance of AMP-activated protein kinase expression and modifying effect of MAPK3/1 in colorectal cancer
AU - Baba, Y.
AU - Nosho, K.
AU - Shima, K.
AU - Meyerhardt, J. A.
AU - Chan, A. T.
AU - Engelman, J. A.
AU - Cantley, L. C.
AU - Loda, M.
AU - Giovannucci, E.
AU - Fuchs, C. S.
AU - Ogino, S.
N1 - Funding Information:
This work was supported by US National Institute of Health (NIH) grants P01 CA87969 (to S Hankinson), P01 CA55075 (to W Willett), P50 CA127003 (to CSF) R01 CA131945 (to ML) and K07 CA122826 (to SO), and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. YB was supported by a fellowship grant from the Uehara Memorial Foundation. KN was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper. The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis. The paper has not been published previously and is not being considered concurrently by any other publication. This paper acknowledges all sources of support for the work.
PY - 2010/9/28
Y1 - 2010/9/28
N2 - Background: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.Methods: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.Results: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).Conclusion: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.
AB - Background: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.Methods: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.Results: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).Conclusion: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.
KW - AMPK
KW - ERK
KW - colon cancer
KW - energy balance
KW - prognosis
UR - https://www.scopus.com/pages/publications/77957231343
U2 - 10.1038/sj.bjc.6605846
DO - 10.1038/sj.bjc.6605846
M3 - Article
C2 - 20808308
AN - SCOPUS:77957231343
SN - 0007-0920
VL - 103
SP - 1025
EP - 1033
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 7
ER -