Abstract
The number of colon cancer cases is increasing worldwide, and type II diabetes patients have an increased risk of developing colon cancer. Diet-borne advanced glycation end-products (AGEs) may promote neoplastic transformation; however, the mechanisms involved remain elusive. The present study helped to define the relationship between dietary AGEs and cancer progression. C2BBe1 adenocarcinoma enterocytes were exposed to 200 µg/mL glycated casein (AGEs-Csn) for up to 24 h. AGEs-Csn exposure resulted in increased cell proliferation, maladaptative changes in SOD and CAT activity and moderate levels of hydrogen peroxide (H2O2) intracellular accumulation. AGEs-Csn activated pro-survival and proliferation signalling, such as the phosphorylation of mTOR (Ser2448) and Akt (Ser473). GSK-3β phosphorylation also increased, potentially inducing extracellular matrix remodelling and thus enabling metastasis. Moreover, AGEs-Csn induced MMP-1, -3, -7, -9 and -10 expression and activated MMP-2 and MMP-9, which are regulators of the extracellular matrix and cytokine functions. AGEs-Csn induced inflammatory responses that included extracellular IL-1β at 6 h; time-dependent increases in IL-8; RAGE and NF-κB p65 upregulation; and IκB inhibition. Co-treatment with anti-RAGE or anti-TNF-α blocking antibodies and AGEs-Csn partially counteracted these changes; however, IL-8, MMP-1 and -10 expression and MMP-9 activation were difficult to prevent. AGEs-Csn perpetuated signalling that led to cell proliferation and matrix remodelling, strengthening the link between AGEs and colorectal cancer aggressiveness.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenocarcinoma / etiology
-
Adenocarcinoma / genetics
-
Adenocarcinoma / metabolism
-
Adenocarcinoma / pathology
-
Antigens, Neoplasm / genetics
-
Antigens, Neoplasm / metabolism
-
Caseins / chemistry
-
Caseins / pharmacology*
-
Catalase / genetics
-
Catalase / metabolism
-
Cell Line, Tumor
-
Colonic Neoplasms / etiology
-
Colonic Neoplasms / genetics
-
Colonic Neoplasms / metabolism
-
Colonic Neoplasms / pathology
-
Enterocytes / drug effects*
-
Enterocytes / metabolism
-
Enterocytes / pathology
-
Extracellular Matrix / drug effects
-
Extracellular Matrix / metabolism
-
Gene Expression Regulation, Neoplastic*
-
Glycation End Products, Advanced / pharmacology*
-
Glycogen Synthase Kinase 3 beta / genetics
-
Glycogen Synthase Kinase 3 beta / metabolism
-
Glycosylation
-
Humans
-
I-kappa B Proteins / genetics
-
I-kappa B Proteins / metabolism
-
Interleukin-1beta / genetics
-
Interleukin-1beta / metabolism
-
Interleukin-8 / genetics
-
Interleukin-8 / metabolism
-
Matrix Metalloproteinase 2 / genetics
-
Matrix Metalloproteinase 2 / metabolism
-
Matrix Metalloproteinase 9 / genetics
-
Matrix Metalloproteinase 9 / metabolism
-
Mitogen-Activated Protein Kinases / genetics
-
Mitogen-Activated Protein Kinases / metabolism
-
Models, Biological
-
NF-kappa B / genetics
-
NF-kappa B / metabolism
-
Phosphorylation
-
Proto-Oncogene Proteins c-akt / genetics
-
Proto-Oncogene Proteins c-akt / metabolism
-
Signal Transduction
-
Superoxide Dismutase / genetics
-
Superoxide Dismutase / metabolism
-
TOR Serine-Threonine Kinases / genetics
-
TOR Serine-Threonine Kinases / metabolism
Substances
-
Antigens, Neoplasm
-
Caseins
-
Glycation End Products, Advanced
-
I-kappa B Proteins
-
IL1B protein, mouse
-
Interleukin-1beta
-
Interleukin-8
-
NF-kappa B
-
Catalase
-
Superoxide Dismutase
-
MTOR protein, human
-
Glycogen Synthase Kinase 3 beta
-
Proto-Oncogene Proteins c-akt
-
TOR Serine-Threonine Kinases
-
MOK protein, human
-
Mitogen-Activated Protein Kinases
-
MMP2 protein, human
-
Matrix Metalloproteinase 2
-
MMP9 protein, human
-
Matrix Metalloproteinase 9