Yang In-Hyoung, Hong Seung-Hyun, Jung Minjung, Ahn Chi-Hyun, Yoon Hye-Jung, Hong Seong Doo, Cho Sung-Dae, Shin Ji-Ae
Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430 USA.
Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430 USA.
Cancer Cell Int. 2020 Aug 26;20:405. doi: 10.1186/s12935-020-01495-2. eCollection 2020.
Despite being one of the leading cancer types in the world, the diagnosis of oral cancer and its suitable therapeutic options remain limited. This study aims to investigate the single and chemosensitizing effects of TW-37, a BH3 mimetic in oral cancer, on human oral cancer cell lines.
We assessed the single and chemosensitizing effects of TW-37 in vitro using trypan blue exclusion assay, Western blotting, DAPI staining, Annexin V-FITC/PI double staining, and quantitative real-time PCR. Mcl-1 overexpression models were established by transforming vector and transient transfection was performed to test for apoptosis.
TW-37 enhanced the cytotoxicity of human oral cancer cell lines by inducing caspase-dependent apoptosis, which correlates with the reduction of the myeloid cell leukemia-1 (Mcl-1) expression via transcriptional and post-translational regulation. The ectopic expression of Mcl-1 partially attenuated the apoptosis-inducing capacity of TW-37 in human oral cancer cell lines. Besides, TW-37 decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr and nuclear translocation in human oral cancer cell lines at the early time points. Furthermore, TW-37 potentiated chemosusceptibility of cryptotanshinone in human oral cancer cell lines by suppressing STAT3-Mcl-1 signaling compared with either TW-37 or cryptotanshinone alone, resulting in potent apoptosis.
This study not only unravels the single and chemosensitizing effects of TW-37 for treatment of human oral cancer but also highlights the likelihood of TW-37 as a good therapeutic strategy to enhance the prognosis of patients with oral cancer in the future.
尽管口腔癌是全球主要的癌症类型之一，但其诊断方法及其合适的治疗选择仍然有限。本研究旨在探讨BH3模拟物TW-37对人口腔癌细胞系的单一作用及化学增敏作用。
我们使用台盼蓝排斥试验、蛋白质免疫印迹法、DAPI染色、膜联蛋白V-FITC/PI双染法和定量实时聚合酶链反应，在体外评估TW-37的单一作用及化学增敏作用。通过转染载体建立Mcl-1过表达模型，并进行瞬时转染以检测细胞凋亡。
TW-37通过诱导半胱天冬酶依赖性凋亡增强人口腔癌细胞系的细胞毒性，这与通过转录和翻译后调控降低髓系细胞白血病-1（Mcl-1）的表达相关。Mcl-1的异位表达部分减弱了TW-37在人口腔癌细胞系中的凋亡诱导能力。此外，TW-37在早期时间点降低了人口腔癌细胞系中酪氨酸磷酸化的信号转导和转录激活因子3（STAT3）及其核转位。此外，与单独使用TW-37或隐丹参酮相比，TW-37通过抑制STAT3-Mcl-1信号通路增强了人口腔癌细胞系对隐丹参酮的化学敏感性，从而导致有效的细胞凋亡。
本研究不仅揭示了TW-37对治疗人口腔癌的单一作用及化学增敏作用，还突出了TW-37作为一种良好的治疗策略在未来改善口腔癌患者预后方面的可能性。
