FLLL32 Triggers Caspase-Mediated Apoptotic Cell Death in Human Oral Cancer Cells by Regulating the p38 Pathway.

Chiao-Wen Lin,Wei-En Yang,Chun-Wen Su,Yi-Tzu Chen,Shun-Fa Yang,Yi-Ping Pan,Chun-Yi Chuang

doi:10.3390/ijms222111860

Abstract

Oral cancer is the most common oral malignant tumor in Taiwan. Although there exist several methods for treatment, oral cancer still has a poor prognosis and high recurrence. FLLL32, a synthetic analog of curcumin with antitumor activity, is currently known to induce melanoma apoptosis and inhibit tumor growth in various cancers. However, few studies have examined the mechanisms of FLLL32 in oral cancer. In this study, we explore whether FLLL32 induces apoptosis in oral cancer. We determined that FLLL32 can inhibit the cell viability of oral cancer. Next, we analyzed the effect of FLLL32 on the cell cycle of oral cancer cells and observed that the proportion of cells in the G2/M phase was increased. Additionally, annexin-V/PI double staining revealed that FLLL32 induced apoptosis in oral cancer cells. Data from the Human Apoptosis Array revealed that FLLL32 increases the expression of cleaved caspase-3 and heme oxygenase-1 (HO-1). FLLL32 activates proteins such as caspase-8, caspase-9, caspase-3, PARP, and mitogen-activated protein kinases (MAPKs) in apoptosis-related molecular mechanisms. Moreover, by using MAPK inhibitors, we suggest that FLLL32 induces the apoptosis of oral cancer cells through the p38 MAPK signaling pathway. In conclusion, our findings suggest that FLLL32 is a potential therapeutic agent for oral cancer by inducing caspase-dependent apoptosis and HO-1 activation through the p38 pathway. We believe that the activation of HO-1 and the p38 pathway by FLLL32 represent potential targets for further research in oral cancer.

Highlights

Introduction published maps and institutional affilOral cancer is the most common oral malignant tumor
The results revealed that the inhibition of the p38 pathway by SB203580 could reverse the cell viability reduction induced by FLLL32 (Figure 7E)
On the basis of the above results, we suggest that FLLL32 regulates caspase-mediated apoptosis and heme oxygenase-1 (HO-1) activation through the p38 signaling pathway (Figure 7F)

Summary

Introduction

Oral cancer is the most common oral malignant tumor. 90% of oral cancers are oral squamous cell carcinoma (OSCC), and the most common sites are the tongue, the upper and lower gums, the floor of the mouth, the upper jaw, and the buccal mucosa [1]. Oral squamous cell carcinoma accounts for about 1–2% of all human malignancies, and it is considered to have a high potential for invasion and metastasis [2]. The most common risk factors for oral cancer include betel nut chewing, smoking, drinking, viruses, radiation, eating habits, and other factors [3,4]. There are many treatments for oral cancer, including surgery, radiation therapy, chemotherapy, and targeted therapy, oral cancer still has delayed clinical detection, without specific biomarkers for the disease, along with a poor prognosis and high recurrence [5]. The loss of control of primary tumors and lymph node metastasis are the main causes of death in patients with oral cancer

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