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. 2010 Sep 28;103(7):1025-33.
doi: 10.1038/sj.bjc.6605846. Epub 2010 Aug 31.

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

Y Baba  1 , K Nosho, K Shima, J A Meyerhardt, A T Chan, J A Engelman, L C Cantley, M Loda, E Giovannucci, C S Fuchs, S Ogino
Affiliations

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

Y Baba et al. Br J Cancer. .

Abstract

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.

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Conflict of interest statement

LCC is Chairman of the Scientific Advisory Board and a minor stockholder of Cell Signaling Technologies, which provides the antibodies against p-AMPK and phospho-p44/42 MAPK that were used in this study. LCC is Founder and Scientific Advisory Board Member of Agios Pharmaceuticals, which has a commercial interest in targeted therapy. No other conflict of interest exists.

Figures

Figure 1
Figure 1
Schematic representation of the AMPK pathway in relation to various molecules. Arrows and lines indicate the pathways potentially related with the complex interaction between AMPK and MAPK3/1. Circles indicate the tissue markers analysed in our current study.
Figure 2
Figure 2
Phosphorylated AMPK and p-MAPK3/1 expression in colorectal cancer. (A) Positive for p-AMPK cytoplasmic expression (arrowheads). (B) Negative for p-AMPK expression (white arrowheads). (C) Positive for p-MAPK3/1 nuclear expression (white arrows). (D) Negative for p-MAPK3/1 expression (block arrow). Stromal cells serve as an internal positive control for p-MAPK3/1 expression (arrow).
Figure 3
Figure 3
Kaplan–Meier curves for colorectal cancer-specific survival. (A) p-AMPK status and survival of colorectal cancer patients. The left panel includes all eligible cases, the middle panel includes p-MAPK3/1-positive cases, and the right panel includes p-MAPK3/1-negative cases. (B) p-MAPK3/1 status and survival of colorectal cancer patients. The left panel includes all eligible cases, the middle panel includes p-AMPK-positive cases, and the right panel includes p-AMPK-negative cases.
See this image and copyright information in PMC

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