Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.
Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
Int J Mol Sci. 2021 Nov 1;22(21):11860. doi: 10.3390/ijms222111860.
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.
口腔癌是台湾最常见的口腔恶性肿瘤。尽管有几种治疗方法，但口腔癌的预后仍然很差，且易复发。FLLL32 是一种具有抗肿瘤活性的姜黄素合成类似物，目前已知可诱导黑色素瘤细胞凋亡，并抑制多种癌症中的肿瘤生长。然而，很少有研究探讨 FLLL32 在口腔癌中的作用机制。在本研究中，我们探讨了 FLLL32 是否能诱导口腔癌细胞凋亡。我们确定 FLLL32 能抑制口腔癌细胞的活力。接下来，我们分析了 FLLL32 对口腔癌细胞周期的影响，观察到 G2/M 期细胞比例增加。此外，Annexin-V/PI 双染显示 FLLL32 诱导口腔癌细胞凋亡。人细胞凋亡 array 数据显示 FLLL32 增加了 cleaved caspase-3 和血红素加氧酶-1（HO-1）的表达。FLLL32 通过凋亡相关分子机制激活了 caspase-8、caspase-9、caspase-3、PARP 和丝裂原活化蛋白激酶（MAPKs）等蛋白。此外，通过使用 MAPK 抑制剂，我们提出 FLLL32 通过 p38 MAPK 信号通路诱导口腔癌细胞凋亡。总之，我们的研究结果表明，FLLL32 通过 p38 通路诱导 caspase 依赖性凋亡和 HO-1 激活，是一种有潜力的口腔癌治疗药物。我们认为 FLLL32 激活 HO-1 和 p38 通路可能是口腔癌进一步研究的潜在靶点。
