CLEFMA Induces the Apoptosis of Oral Squamous Carcinoma Cells through the Regulation of the P38/HO-1 Signalling Pathway

Simple Summary Oral squamous cell carcinoma (OSCC) constitutes more than 90% of head and neck cancers and a high prevalence rate in some parts of the world. Alcohol consumption, use of snuff, and several other factors including genetic makeup are associated with 90% of patients with oral cancer. However, the molecular mechanisms involved in CLEFMA-mediated apoptotic cell death of human OSCC remain poorly understood. Our study found that CLEFMA induced the heme oxygenase-1 (HO-1) level by activating p38 mitogen-activated protein kinase signalling cascade and subsequently activated caspase-dependent cell death, which is critical to the anti-cancer effect in OSCC. The purpose of this research was to evaluate the impact and the underlying molecular mechanism of CLEFMA-induced cell death in human OSCC. The anti-tumour properties of CLEFMA in oral cancer were explored using colony formation, flow cytometry, human apoptosis array, Western blot, and immunohistochemistry assays. The in vivo anti-tumour effect of CLEFMA administered by oral gavage was evaluated using SCC-9-derived xenograft-bearing nude mouse models. CLEFMA significantly suppressed colony formation and elicited cellular apoptosis in oral cancer cells. CLEFMA treatment remarkably increased phosphorylated p38 and HO-1 along with cleavage of poly ADP-ribose polymerase and activation of caspase-8, -9, and -3 in HSC-3 and SCC-9 cells. Administration of HO-1 small interfering RNA significantly protected the cells from CLEFMA-induced caspase-3, -8, and -9 activation. Attenuation of p38 activity by the pharmacologic inhibitor SB203580 dramatically reduced CLEFMA-induced caspase-3, -8, and -9 activation and HO-1 expression in OSCC. The subcutaneous murine xenograft models showed that CLEFMA in vivo suppressed tumour growth in implanted SCC-9 cells. All of these findings indicated that CLEFMA induced apoptosis through the p38-dependent rise in HO-1 signal transduction cascades in OSCC.

Automated summary

This study demonstrates that CLEFMA induces apoptosis in oral squamous cell carcinoma (OSCC) through the activation of a p38-dependent HO-1 signaling cascade.