Nε-(1-Carboxymethyl)-L-lysine, an advanced glycation end product, exerts malignancy on chondrosarcoma via the activation of cancer stemness

Abstract

Despite epidemiological evidence that suggests diabetes mellitus is a risk factor for cancer, the link between diabetes mellitus and primary bone cancer is rarely discussed. Chondrosarcomas are primary malignant cartilage tumors with poor prognosis and high metastatic potential. It remains unclear whether hyperglycemia affects the stemness and malignancy of chondrosarcoma cells. Nε-(1-Carboxymethyl)-L-lysine (CML), an advanced glycation end product (AGE), is a major immunological epitope detected in the tissue proteins of diabetic patients. We hypothesized that CML could enhance cancer stemness in chondrosarcoma cells. CML enhanced tumor-sphere formation and the expression of cancer stem cell markers in human chondrosarcoma cell lines. Migration and invasion ability and the epithelial-mesenchymal transition (EMT) process were also induced by CML treatment. Moreover, CML increased the protein expression levels of the receptor for AGE (RAGE), phosphorylated NFκB-p65, and decreased the phosphorylation of AKT and GSK-3. We also found that hyperglycemia with high CML levels facilitated tumor metastasis, whereas tumor growth was not affected in the streptozotocin (STZ)-induced diabetic NOD/SCID tumor xenograft mouse models. Our results indicate that CML enhances chondrosarcoma stemness and metastasis, which may reveal the relationship between AGE and bone cancer metastasis.

Keywords: Cancer stemness; Chondrosarcoma; Diabetes mellitus; Metastasis; Nε-(1-Carboxymethyl)-L-lysine.