4.7 Article

Curcumol Exerts Antitumor Effect via Inhibiting EGFR-Akt-Mcl-1 Signaling

Journal

AMERICAN JOURNAL OF CHINESE MEDICINE
Volume 51, Issue 3, Pages 741-760

Publisher

WORLD SCIENTIFIC PUBL CO PTE LTD
DOI: 10.1142/S0192415X23500350

Keywords

Oral Squamous Cell Carcinoma; Epidermal Growth Factor Receptor; Mcl-1; Ubiquitination; Curcumol

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The dysfunction of EGFR signaling is crucial in the development of OSCC, and this study confirms the overexpression of EGFR in OSCC tumor tissues. Depletion of EGFR inhibits OSCC cell growth, while the natural compound curcumol shows anti-tumor effects by downregulating Mcl-1. Curcumol inhibits the EGFR-Akt signal pathway, resulting in Mcl-1 phosphorylation and degradation. Furthermore, curcumol effectively suppresses tumor growth in vivo and Mcl-1 expression correlates with p-EGFR and p-Akt in OSCC tumor tissues.
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 in vitro and in vivo. 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 beta-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 in vivo. 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.

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