Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P. R. China.
Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P. R. China.
Am J Chin Med. 2023;51(3):741-760. doi: 10.1142/S0192415X23500350. Epub 2023 Mar 2.
Dysfunction of epidermal growth factor receptor (EGFR) signaling plays a critical role in the tumorigenesis of oral squamous cell carcinoma (OSCC). In the present study, the data analysis results of immunohistochemistry and the TCGA database verified that the expression of EGFR is significantly upregulated in OSCC tumor tissues, and depletion of EGFR inhibits the growth of OSCC cells and . Moreover, these results showed that the natural compound, curcumol, exhibited a profound antitumor effect on OSCC cells. Western blotting, MTS, and immunofluorescent staining assays indicated that curcumol inhibited cell proliferation and induced intrinsic apoptosis in OSCC cells via downregulating myeloid cell leukemia 1 (Mcl-1). A mechanistic study revealed that curcumol inhibited the EGFR-Akt signal pathway, which activated GSK-3[Formula: see text]-mediated Mcl-1 phosphorylation. Further research showed that curcumol-induced Mcl-1 Ser159 phosphorylation is required to disrupt the interaction between deubiquitinase JOSD1 and Mcl-1 and eventually induce Mcl-1 ubiquitination and degradation. In addition, curcumol administration can effectively inhibit CAL27 and SCC25 xenograft tumor growth and is well-tolerated . Finally, we demonstrated that Mcl-1 is upregulated and positively correlates with p-EGFR and p-Akt in OSCC tumor tissues. Collectively, the present results provide new insights into the antitumor mechanism of curcumol, identifying it as an attractive therapeutic agent that reduces Mcl-1 expression and inhibits OSCC growth. Targeting EGFR/Akt/Mcl-1 signaling could be a promising option in the clinical treatment of OSCC.
表皮生长因子受体 (EGFR) 信号功能障碍在口腔鳞状细胞癌 (OSCC) 的肿瘤发生中起着关键作用。在本研究中，免疫组织化学数据分析结果和 TCGA 数据库验证了 EGFR 在 OSCC 肿瘤组织中的表达显著上调，并且 EGFR 的耗竭抑制了 OSCC 细胞的生长。此外，这些结果表明天然化合物姜黄素对 OSCC 细胞具有显著的抗肿瘤作用。Western blot、MTS 和免疫荧光染色实验表明，姜黄素通过下调髓样细胞白血病 1 (Mcl-1) 抑制 OSCC 细胞的增殖并诱导其内在凋亡。机制研究表明，姜黄素抑制 EGFR-Akt 信号通路，该通路激活 GSK-3[Formula: see text]-介导的 Mcl-1 磷酸化。进一步的研究表明，姜黄素诱导的 Mcl-1 Ser159 磷酸化对于破坏去泛素酶 JOSD1 和 Mcl-1 之间的相互作用并最终诱导 Mcl-1 泛素化和降解是必需的。此外，姜黄素给药可以有效地抑制 CAL27 和 SCC25 异种移植肿瘤的生长，且具有良好的耐受性。最后，我们证明 Mcl-1 在 OSCC 肿瘤组织中上调，并与 p-EGFR 和 p-Akt 呈正相关。总之，这些结果为姜黄素的抗肿瘤机制提供了新的见解，将其鉴定为一种有吸引力的治疗剂，可降低 Mcl-1 表达并抑制 OSCC 生长。靶向 EGFR/Akt/Mcl-1 信号通路可能是 OSCC 临床治疗的有前途的选择。
