title: Prognostic significance of AMP-activated protein kinase expression and modifying effect of MAPK3/1 in colorectal 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Room JF-215C, Boston, MA 02115, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Baba
authors.forename: K
authors.initials: K
authors.lastname: Nosho
authors.forename: K
authors.initials: K
authors.lastname: Shima
authors.forename: J A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: A T
authors.initials: AT
authors.lastname: Chan
authors.forename: J A
authors.initials: JA
authors.lastname: Engelman
authors.forename: L C
authors.initials: LC
authors.lastname: Cantley
authors.forename: M
authors.initials: M
authors.lastname: Loda
authors.forename: E
authors.initials: E
authors.lastname: Giovannucci
authors.forename: C S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: S
authors.initials: S
authors.lastname: Ogino
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000378:metabolism* / Q000401:mortality; D019175:DNA Methylation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C491297:MSI1 protein, human; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases
references.citation: Cancer Res. 1998 Nov 15;58(22):5248-57
references.pmid: 9823339
references.citation: Gut. 2009 Jan;58(1):90-6
references.pmid: 18832519
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: Br J Cancer. 2005 Jun 20;92(12):2206-15
references.pmid: 15928662
references.citation: Neoplasia. 2008 Jun;10(6):534-41
references.pmid: 18516290
references.citation: Nat Rev Cancer. 2009 Aug;9(8):563-75
references.pmid: 19629071
references.citation: Br J Cancer. 2010 Apr 27;102(9):1384-90
references.pmid: 20424616
references.citation: J Clin Oncol. 2005 Sep 20;23(27):6771-90
references.pmid: 16170185
references.citation: Cancer Res. 2008 Feb 1;68(3):759-66
references.pmid: 18245476
references.citation: Mod Pathol. 2006 Jan;19(1):59-68
references.pmid: 16118624
references.citation: Cell Cycle. 2009 Mar 1;8(5):788-91
references.pmid: 19221486
references.citation: Br J Cancer. 2009 May 19;100(10):1666-73
references.pmid: 19436307
references.citation: PLoS One. 2009 Nov 23;4(11):e7951
references.pmid: 19956740
references.citation: Nat Rev Cancer. 2008 Dec;8(12):915-28
references.pmid: 19029956
references.citation: Mod Pathol. 2009 Jul;22(7):922-32
references.pmid: 19430421
references.citation: PLoS One. 2009;4(3):e4771
references.pmid: 19274086
references.citation: Nature. 2007 Aug 16;448(7155):807-10
references.pmid: 17676035
references.citation: Cancer Prev Res (Phila). 2008 Oct;1(5):369-75
references.pmid: 19138981
references.citation: J Biol Chem. 2010 May 7;285(19):14617-27
references.pmid: 20220132
references.citation: N Engl J Med. 2007 May 24;356(21):2131-42
references.pmid: 17522398
references.citation: Mol Cell. 2009 Jan 30;33(2):237-47
references.pmid: 19187764
references.citation: Int J Cancer. 2008 Jun 15;122(12):2767-73
references.pmid: 18366060
references.citation: J Mol Diagn. 2007 Jul;9(3):305-14
references.pmid: 17591929
references.citation: Br J Cancer. 2010 Jan 5;102(1):165-72
references.pmid: 19997103
references.citation: Hum Mol Genet. 2009 Apr 15;18(R1):R94-100
references.pmid: 19297407
references.citation: BMJ. 2005 Jun 4;330(7503):1304-5
references.pmid: 15849206
references.citation: Diabetes Care. 2006 Feb;29(2):254-8
references.pmid: 16443869
references.citation: Cancer Prev Res (Phila). 2009 Apr;2(4):301-9
references.pmid: 19336731
references.citation: Br J Cancer. 2009 May 19;100(10):1540-8
references.pmid: 19384300
references.citation: J Mol Diagn. 2008 Jan;10(1):13-27
references.pmid: 18165277
references.citation: Br J Cancer. 2009 Oct 20;101(8):1282-9
references.pmid: 19773751
references.citation: BMC Cancer. 2009 Sep 01;9:307
references.pmid: 19723334
references.citation: J Clin Oncol. 2008 Dec 10;26(35):5713-20
references.pmid: 18955444
references.citation: Am J Surg Pathol. 2006 Sep;30(9):1175-83
references.pmid: 16931963
references.citation: Virchows Arch. 2007 Feb;450(2):151-9
references.pmid: 17149612
references.citation: J Mol Diagn. 2006 Nov;8(5):582-8
references.pmid: 17065427
references.citation: J Clin Oncol. 2010 Jan 20;28(3):466-74
references.pmid: 20008640
references.citation: J Biol Chem. 2008 Feb 15;283(7):3731-42
references.pmid: 18079115
references.citation: PLoS One. 2008;3(11):e3698
references.pmid: 19002263
references.citation: Cancer Res. 2007 Jul 15;67(14):6745-52
references.pmid: 17638885
references.citation: Cancer Causes Control. 2010 Aug;21(8):1237-45
references.pmid: 20383576
references.citation: J Biol Chem. 2001 Jun 1;276(22):19102-10
references.pmid: 11262401
references.citation: J Mol Diagn. 2005 Aug;7(3):413-21
references.pmid: 16049314
references.citation: Nat Rev Cancer. 2007 Apr;7(4):295-308
references.pmid: 17384584
references.citation: J Mol Diagn. 2010 Mar;12(2):177-83
references.pmid: 20093385
references.citation: Br J Cancer. 2009 Nov 17;101(10):1749-57
references.pmid: 19844231
references.citation: J Natl Cancer Inst. 2008 Dec 3;100(23):1734-8
references.pmid: 19033568
references.citation: Gut. 2006 Jul;55(7):1000-6
references.pmid: 16407376
references.citation: Nat Genet. 2006 Jul;38(7):787-93
references.pmid: 16804544
references.citation: Mol Cancer Ther. 2009 Apr;8(4):834-43
references.pmid: 19372556
references.citation: Cancer Res. 2006 Oct 15;66(20):10057-63
references.pmid: 17047069
references.citation: Br J Cancer. 2010 Jan 5;102(1):151-61
references.pmid: 19935791
references.citation: Cell. 2005 Apr 22;121(2):179-93
references.pmid: 15851026
references.citation: Clin Cancer Res. 2006 Jul 1;12(13):3935-41
references.pmid: 16818690
references.citation: Br J Cancer. 2009 Aug 18;101(4):715-21
references.pmid: 19603018
references.citation: Neoplasia. 2006 Jun;8(6):458-64
references.pmid: 16820091