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

Abstract

Abstract. An irreversible non-enzymatic reaction between carbohydrates and proteins results in the formation of advanced glycation end products (AGEs). AGEs have been demonstrated to be a risk factor of complications in patients with diabetes mellitus (DM). Previous studies have suggested that patients with DM exhibit a higher rate of metastasis of oral cancer and a lower cancer-associated survival rate. The receptor for AGEs (RAGE) has been associated with angiogenesis and an increase in cancer malignancy. Previous studies have suggested that AGE-RAGE regulates cell migration via extracellular signal-regulated kinase (ERK) phosphorylation. Nuclear factor-erythroid 2-related factor 2 (Nrf-2) is associated with the regulation of tumor protein p53 (p53) and the apoptotic response of oral cancer cells. AGEs are associated with oral cancer; however, the mechanism underlying this association remains to be elucidated. The present study hypothesized that AGEs regulate Nrf-2 and downstream pathways through ERK phosphorylation. The results of the current study demonstrated that AGEs inhibit the expression of Nrf-2, p53 and Bcl-2 associated x apoptosis regulator, and increase the expression of apoptosis regulator Bcl-x protein. The effect of AGEs was inhibited through the use of the PD98059. The present study demonstrated that AGEs regulate the downstream pathways Nrf-2 and Bcl-xl via ERK phosphorylation. It is suggested that AGEs regulate the survival of oral cancer cells via Nrf-2 and Bcl-xl through p53 regulation, which explains the poor prognosis of patients with DM who have oral cancer.

Wine Consumption and Oral Cavity Cancer: Friend or Foe, Two Faces of Janus

“…The reduction of MMP-9 activity by resveratrol is related to the suppression of the phosphorylation of ERK and JNK induced by TPA [115]. Using the oral cancer cell line SAS, it was observed that resveratrol induces apoptosis through nuclear factor-erythroid 2-related factor 2, heme oxygenase 1, tumor protein p53 and Bax signaling pathways [117].…”

Role and Mechanisms of RAGE-Ligand Complexes and RAGE-Inhibitors in Cancer Progression

“…The formed AGEs enhance cancer cell migration through the expression of vascular endothelial growth factor (VEGF), NF-κB, and extracellular signal-regulated kinase (ERK) pathways [13,21]. AGEs-RAGE axis has induced cancer cell progression in colon, breast, oral, prostate, and neuroblastoma cell lines (Table 1), and AGEs-RAGE axis can enhance cancer progression through regulation of the pathways and molecules described below and illustrated in Figure 1 [21][22][23][24][25][26][27]. The effects of receptor for advanced glycation end product (RAGE)-ligands on cancer progression.…”

“…Nuclear factor (erythroid-derived 2)-like 2 (Nrf-2): Keap1 complex could lead to cancer cell proliferation and metastasis through regulation of p53 apoptotic pathway [23,40]. Activated AGEs-RAGE axis in oral cancer (SAS) cell line led to downregulation of Nrf-2 that consequently facilitated the spread of cancer cells [23]. The authors postulated that downregulation of Nrf-2 is associated with the downregulation of p53 of oral cancer cells via heme oxygenase (HO-1).…”

“…A number of different studies demonstrated that induction of AGEs led to upregulation of phosphatidylinositide 3-kinase (PI3K) [22,33], protein kinase B (Akt) [22], NF-κB [13,[42][43][44], and VEGF [21,24] and downregulation of p53 [23] in various cancer cell types (Table 1). Based on these studies, we propose that activation of the AGEs-RAGE axis leads to upregulation of PI3K and subsequent phosphorylation of Akt.…”

A 2-es típusú diabetes mellitus prevalenciájának változása szájüregi carcinomás betegek körében

“…Az áttétképződésben szerepet játszik a DM-ben megemelkedett mátrixmetalloproteináz-szint is [8,18]. Tartósan magas vércukorszint esetén emelkedik a glikációs végtermékek szintje és ennek révén a RAGE (receptor for advanced glycation end products) expressziója, amely a carcinomák invazivitásának szabályozójaként elősegíti a tumorszóródást [19,20]. A hyperglykaemia hatására fokozódik a vér alakos elemeinek agglutinációja, amely microembolisatio révén érelzáródást és ennek következtében szöveti hypoxiát okoz [21,22].…”