Abstract
BackgroundOverexpression of survivin plays a crucial role in tumorigenesis and correlates with poor prognosis in human malignancies. Thus, survivin has been proposed as an attractive target for new anti-tumor interventions.MethodsA natural product library was used for natural compound screening through MTS assay. The expression of survivin in oral squamous cell carcinoma (OSCC) and the inhibitory effect of xanthohumol (XN) on OSCC were examined by anchorage-dependent and -independent growth assays, immunoblot, immunofluorescence, immunohistochemical staining, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiment.ResultsSurvivin is highly expressed in OSCC patient-derived tissues and cell lines. Knockout of survivin reduced the tumorigenic properties of OSCC cells in vitro and in vivo. With a natural compound screening, we identified that xanthohumol inhibited OSCC cells by reducing survivin protein level and activating mitochondrial apoptotic signaling. Xanthohumol inhibited the Akt-Wee1-CDK1 signaling, which in turn decreased survivin phosphorylation on Thr34, and facilitated E3 ligase Fbxl7-mediated survivin ubiquitination and degradation. Xanthohumol alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors.ConclusionOur findings indicate that targeting survivin for degradation might a promising strategy for OSCC treatment.
Highlights
Overexpression of survivin plays a crucial role in tumorigenesis and correlates with poor prognosis in human malignancies
As compared to the immortalized oral epithelial cell, survivin was expressed at a relatively higher level in all tested oral squamous cell carcinoma (OSCC) cell lines (Fig. 1b). These results indicate that high level of survivin might play a crucial role in the oncogenesis of OSCC
A similar inhibitory effect was observed in SCC25 xenograft tumors (Fig. 1h-j). These results support the notion that survivin is overexpressed in OSCC tissues and cell lines, and that knockout of survivin reduces the tumorigenic properties of OSCC cells
Summary
Overexpression of survivin plays a crucial role in tumorigenesis and correlates with poor prognosis in human malignancies. Survivin has been proposed as an attractive target for new anti-tumor interventions. The highest incidence of OSCC is observed in South Asian countries and regions, such as India, Sri Lanka, and the south-central of China, which are caused by the high rates of cigarette smoking and areca nut use in these areas [5,6,7]. The improvements in early diagnosis and surgical treatment over the past decades, OSCC usually progresses rapidly and presents high mortality rates, especially in patients with an advanced stage, and no targeted therapy is used in clinic for OSCC treatment currently [3, 6,7,8,9]. A better understanding of the mechanisms of OSCC oncogenesis and development of novel anti-tumor targets and drugs, are still the urgent demand for OSCC treatment
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Experimental & Clinical Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
