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

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.

Curcumin analog HO‐3867 triggers apoptotic pathways through activating JNK1/2 signalling in human oral squamous cell carcinoma cells

“…The inhibitors were U0126, 46 JNK‐IN‐8 47 and SB203580 48 for blocking the phosphorylation of ERK1/2, JNK1/2 and p38 respectively. According to previous studies, 49,50 after 2‐hour pretreatments of U0126 (10 µM), JNK‐IN‐8 (10 µM) and SB203580 (10 µM), cells were administered with HO‐3867 (20 µM) for another 24 h. We found the treatment of JNK‐IN‐8 was able to attenuate the formation of the active form of caspase 3, caspase 8, caspase 9 and PARP in SCC‐9 cells (Figure 7A). Moreover, as shown in Figure 7B, inhibition of JNK1/2 pathway using JNK‐IN‐8 (10 µM) effectively reduced the apoptotic pathway as the active form of caspase 3, caspase 8, caspase 9 and PARP were reduced in HSC‐3 cells (Figure 7B).…”

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

“…Upstream of Akt, downregulation of the MAPK/ERK protein serine kinase MEK2 (MA2K2) was also reported (Chiu et al, 2021), thus, effectively, inhibiting proliferation and inducing apoptosis by curcuminoids in cancer cells can involve the p38 MAPK pathway (He et al, 2021;Su et al, 2021) (Figure 3). Blocking ERK1/2 expression in glioma cells by curcumin was also observed in another study, confirming that the MAPK signaling pathway is a potential target (Wang P. et al, 2021).…”

Transgelin-2 Involves in the Apoptosis of Colorectal Cancer Cells Induced by Tanshinone-IIA

“…Some studies reported that p38MAPK signal pathway proteins may be related to the regulation of apoptosis genes [ 33 ], or play a role in antitumor drugs activity [ 34 ]. Blockage of the p38MAPK pathway inhibits tumor cells apoptosis [ 35 ]. However, no study has examined the role p38MAPK plays in TanIIA–induced apoptosis in human colorectal tumor cells.…”