Advanced glycation end products (AGEs) are produced in response to a high-
glucose environment and oxidative stress and exacerbate various diseases. Nε-(
Carboxymethyl)lysine (CML) is an AGE that is produced by the glycation of
lysine residues of
proteins. There are a few reports on alterations in
protein function due to CML modification; however, its association with
cancer is not clear. We investigated the significance of CML modification in high mobility group box protein-1 (
HMGB1), a
cytokine that is significantly associated with
cancer progression. Treatment of the
gastric cancer cell lines TMK1 and MKN74 with
glyoxal or
glucose resulted in increased CML modification compared to untreated cells. CML-HMGB1 was modified via oxidation and more pronouncedly activated the receptor for AGE and downstream AKT and NF-κB compared to naïve
HMGB1 and oxidized
HMGB1. CML-HMGB1 bound with reduced affinity to
DNA and
histone H3, resulting in enhanced extranuclear translocation and extracellular secretion. Treatment of
gastric cancer cells with CML-HMGB1 enhanced cell proliferation and invasion, sphere formation, and protection from
thapsigargin-induced apoptosis, and decreased
5-FU sensitivity in comparison to
HMGB1. Further, CML-HMGB1 was detected at various levels in all the 10
gastric cancer tumor specimens.
HMGB1 levels correlated with primary
tumor progression and distant
metastasis, whereas CML-HMGB1 levels were associated with primary
tumor progression,
lymph node metastasis, distant
metastasis, and stage. In addition, CML-HMGB1 levels correlated with oxidative stress in
cancer tissues and resistance to
neoadjuvant therapy. Therefore, CML modification of
HMGB1 enhanced the
cancer-promoting effect of
HMGB1. In this study, CML-HMGB1 has been highlighted as a new therapeutic target, and analysis of the molecular structure of CML-HMGB1 is desired in the future.