Abstract
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.
Highlights
Gastric cancer is the third leading cause of cancer deaths in Japan [1]
We investigated the formation of CML in cancer-related proteins after treating the human gastric cancer cell line TMK1 with glyoxal (GLX) or high-concentration glucose (GLC) (Figure 1A)
GLX and GLC treatment increased the levels of CML-modified high-mobility group box-1 (HMGB1) in the culture medium, which were higher in the culture media of TMK1 cells than in those of other cells (Figure 1D)
Summary
Diagnosis and early endoscopic treatment have improved the 5-year survival rate of gastric cancer patients (73.1%) [2]. The 5-year survival rate for advanced gastric cancer still remains poor at 47.2 and 7.3% for stages III and IV, respectively [2]. Taguchi et al reported that high-mobility group box-1 (HMGB1) promotes the progression and metastasis of various cancer types [3]. We have previously reported the involvement of HMGB1 in malignancy in gastric, colorectal, prostate, and oral cancers [4,5,6,7,8,9]. The high expression of HMGB1 along with that of its receptor, i.e., receptor for advanced glycation end products (RAGE), correlates well with the progression of gastric cancer [4]. HMGB1 provides cancer cells’ proliferation, invasion, anti-apoptotic survival, and metastatic ability [10]
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