Chen Hsien-Lin, Lo Yi-Hao, Lin Chieh-Liang, Lee Tzong-Huei, Leung Wan, Wang Shih-Wei, Lin In-Pin, Lin Mei-Ying, Lee Chien-Hsing
Division of General Surgery, Department of Surgery, Chi Mei Medical Center, Liouying, Tainan 73657, Taiwan.
Department of Family Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81342, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.; Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
Biomed Pharmacother. 2022 Sep;153:113351. doi: 10.1016/j.biopha.2022.113351. Epub 2022 Jul 1.
Trichodermin (TCD), a trichothecene first isolated from marine Trichoderma viride, is an inhibitor of eukaryotic protein synthesis. However, the potential effects of TCD on human oral squamous cell carcinoma (OSCC) cells and the underlying molecular mechanisms remain unknown. In this study, the exposure of OSCC cells (Ca922 and HSC-3 cells) to TCD suppressed cell proliferation assessed using MTT assays and colony formation assays. TCD inhibited the migration and invasion of OSCC cells (Ca922 and HSC-3 cells) through the downregulation of matrix metalloproteinase 9. After treatment of OSCC cells with TCD, the G2/M phase was arrested, caspase-related apoptosis (cleaved caspase-3 and PARP expression) was induced, and the protein level of x-linked inhibitor of apoptosis was reduced. Meanwhile, the TCD-induced cell death was reversed by the pan-caspase inhibitor Z-VAD-FMK. Furthermore, TCD diminished mitochondrial membrane potential, mitochondrial oxidative phosphorylation and glycolytic function in OSCC cells. In addition, TCD decreased the levels of histone deacetylase 2 (HDAC-2) and downstream signaling proteins, including phosphorylated STAT3 and NF-κB. Finally, TCD significantly suppressed tumor growth in a zebrafish OSCC xenotransplantation model. Overall, this evidence demonstrates that TCD is a novel promising strategy for the treatment of OSCCs.
曲古抑菌素（TCD）是一种最初从海洋绿色木霉中分离出的单端孢霉烯族毒素，是真核生物蛋白质合成的抑制剂。然而，TCD对人口腔鳞状细胞癌（OSCC）细胞的潜在影响及其潜在分子机制尚不清楚。在本研究中，用MTT法和集落形成试验评估，OSCC细胞（Ca922和HSC-3细胞）暴露于TCD后，细胞增殖受到抑制。TCD通过下调基质金属蛋白酶9抑制OSCC细胞（Ca922和HSC-3细胞）的迁移和侵袭。用TCD处理OSCC细胞后，细胞停滞于G2/M期，诱导半胱天冬酶相关凋亡（裂解的半胱天冬酶-3和PARP表达），凋亡抑制蛋白x连锁抑制因子的蛋白水平降低。同时，泛半胱天冬酶抑制剂Z-VAD-FMK可逆转TCD诱导的细胞死亡。此外，TCD降低了OSCC细胞的线粒体膜电位、线粒体氧化磷酸化和糖酵解功能。此外，TCD降低了组蛋白去乙酰化酶2（HDAC-2）和下游信号蛋白的水平，包括磷酸化的信号转导和转录激活因子3（STAT3）和核因子κB（NF-κB）。最后，在斑马鱼OSCC异种移植模型中，TCD显著抑制肿瘤生长。总体而言，这些证据表明TCD是一种治疗OSCC的有前景的新策略。
