Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, 250012, China.
Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China.
Int J Biol Sci. 2022 Jan 1;18(2):473-490. doi: 10.7150/ijbs.65824. eCollection 2022.
Microtubules, a major target in oral squamous cell carcinoma (OSCC) chemotherapy, contribute to multiple malignant biological behaviors, including proliferation, migration, and epithelial-mesenchymal transition (EMT). Surpassing traditional tubulin inhibitors, ID09 emerges with brilliant solubility, photostability, and drug-sensitivity in multidrug-resistant cells. Its anti-tumor effects have been briefly verified in lung adenocarcinoma and hepatocellular carcinoma. However, whether OSCC is sensitive to ID09 and the potential mechanisms remain ambiguous, which are research purposes this study aimed to achieve. Various approaches were applied, including clone formation assay, flow cytometry, wound healing assay, Transwell assay, cell counting kit-8 assay, Western blot, qRT-PCR, and experiment. The experimental results revealed that ID09 not only contributed to cell cycle arrest, reduced migration, and reversed EMT, but accelerated mitochondria-initiated apoptosis. Remarkably, Western blot detected diminishment in expression of Mcl-1 due to the deactivation of Ras-Erk pathway, resulting in ID09-induced apoptosis, proliferation and migration suppression, which could be offset by Erk1/2 phosphorylation agonist Ro 67-7476. This study initially explored the essential role Mcl-1 played and the regulatory effect of Ras-Erk pathway in anti-cancer process triggered by tubulin inhibitor, broadening clinical horizon of tubulin inhibitors in oral squamous cell carcinoma chemotherapy application.
微管是口腔鳞状细胞癌 (OSCC) 化疗的主要靶点，它参与了多种恶性生物学行为，包括增殖、迁移和上皮-间充质转化 (EMT)。ID09 超越了传统的微管抑制剂，在多药耐药细胞中具有出色的溶解性、光稳定性和药物敏感性。它在肺腺癌和肝细胞癌中的抗肿瘤作用已得到初步验证。然而，OSCC 是否对 ID09 敏感以及潜在的机制仍不清楚，这是本研究旨在实现的研究目的。本研究采用了克隆形成实验、流式细胞术、划痕愈合实验、Transwell 实验、细胞计数试剂盒-8 实验、Western blot、qRT-PCR 等多种方法。实验结果表明，ID09 不仅导致细胞周期停滞、迁移减少和 EMT 逆转，还促进了线粒体起始的细胞凋亡。值得注意的是，Western blot 检测到由于 Ras-Erk 通路失活导致 Mcl-1 表达减少，从而引发 ID09 诱导的细胞凋亡、增殖和迁移抑制，这种抑制可以通过 Erk1/2 磷酸化激动剂 Ro 67-7476 来抵消。本研究初步探讨了 Mcl-1 在微管抑制剂诱导的抗癌过程中的重要作用和 Ras-Erk 通路的调节作用，拓宽了微管抑制剂在口腔鳞状细胞癌化疗应用中的临床视野。
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