Cell Migration Is Regulated by AGE-RAGE Interaction in Human Oral Cancer Cells In Vitro

Abstract

Advanced glycation end products (AGEs) are produced in an irreversible non-enzymatic reaction of carbohydrates and proteins. Patients with diabetes mellitus (DM) are known to have elevated AGE levels, which is viewed as a risk factor of diabetes-related complications. In a clinical setting, it has been shown that patients with oral cancer in conjunction with DM have a higher likelihood of cancer metastasis and lower cancer survival rates. AGE-RAGE (a receptor of AGEs) is also correlated with metastasis and angiogenesis. Recent studies have suggested that the malignancy of cancer may be enhanced by glyceraldehyde-derived AGEs; however, the underlying mechanism remains unclear. This study examined the apparently close correlation between AGE-RAGE and the malignancy of SAS oral cancer cell line. In this study, AGEs increased ERK phosphorylation, enhanced cell migration, and promoted the expression of RAGE, MMP2, and MMP9. Using PD98059, RAGE antibody, and RAGE RNAi to block RAGE pathway resulted in the inhibition of ERK phosphorylation. Cell migration, MMP2 and MMP9 expression were also reduced by this treatment. Our findings demonstrate the importance of AGE-RAGE with regard to the malignancy of oral cancer, and help to explain the poor prognosis of DM subjects with oral cancer.

Advanced glycation end products influence oral cancer cell survival via Bcl-xl and Nrf-2 regulation in vitro

“…A previous study by our group revealed that AGEs regulate oral cancer cell migration via the ERK signaling pathway (17). The results demonstrated the mechanism by which AGEs regulate p53 via ERK and downstream Nrf-2 and Bcl-xl.…”

“…Previous studies have demonstrated that cancer malignancy can be promoted by AGEs (14)(15)(16). Furthermore, the migration of oral cancer cells has been revealed to be increased by the receptor for AGEs (17). In a clinical setting, patients with DM exhibit a higher rate of metastasis of oral cancer and a lower cancer-associated survival rate (18).…”

“…A previous study by our group demonstrated that AGEs regulate cell migration via extracellular signal-regulated kinase (ERK) phosphorylation (17). Therefore, it was hypothesized that AGEs regulate Nrf-2 and downstream signaling pathways through ERK phosphorylation.…”

Carboxymethyllysine, an Advanced Glycation End-Product, Promotes the Invasion and Migration of Lung Cancer A549 Cells

“…These findings suggested that CML might be able to facilitate NSCLC metastasis. Ko et al [17] indicated that AGEs favored invasion and migration of oral cancer cells. Takino et al [14] reported that glyceraldehyde-derived AGEs benefited the migration of A549 cells.…”

Role of Exogenous Advanced Glycation End Products in Oral Carcinogenesis: A Review

“…Expression of MMP has been associated with cell migration and metastasis in OSCC [29][30][31]. Thus, AGEs through their influence on MMPs contribute to both tumor aggressiveness and invasive nature of the tumor.…”