Abstract
Cutaneous squamous-cell carcinoma (cSCC) is one of most common type of non-black skin cancer. The malignancy degree and the death risk of cSCC patients are significantly higher than basal cell carcinoma patients. GL-V9 is a synthesized flavonoid derived from natural active ingredient wogonin and shows potent growth inhibitory effects in liver and breast cancer cells. In this study, we investigated the anti-cSCC effect and the underlying mechanism of GL-V9. The results showed that GL-V9 induced both apoptosis and autophagy in human cSCC cell line A431 cells, and prevented the growth progression of chemical induced primary skin cancer in mice. Metabolomics assay showed that GL-V9 potentially affected mitochondrial function, inhibiting glucose metabolism and Warburg effect. Further mechanism studies demonstrated that AKT played important roles in the anti-cSCC effect of GL-V9. On one hand, GL-V9 suppressed AKT-modulated mitochondrial localization of HK2 and promoted the protein degradation of HK2, resulting in cell apoptosis and glycolytic inhibition. On the other hand, GL-V9 induced autophagy via inhibiting Akt/mTOR pathway. Interestingly, though the autophagy induced by GL-V9 potentially antagonized its effect of apoptosis induction, the anti-cSCC effect of GL-V9 was not diluted. All above, our studies suggest that GL-V9 is a potent candidate for cSCC treatment.
Highlights
Cutaneous squamous cell carcinoma, originating from the epidermis or adnexal keratinocytes, is one of the highest incidence of non-melanocytic skin carcinoma, only second to basal cell carcinoma
The results demonstrated that GL-V9 caused mitochondrial dysfunction of A431 cells and induced them in cytoplasm, suggesting GL-V9 promoted the release of cyt-c and apoptosis-inducing factor (AIF) from mitochondria apoptosis via mitochondrial-mediated pathway
These results suggested that the autophagy induced by high concentration of GL-V9 potentially antagonized the effect of apoptosis induction, which might be associated with the of GL-V9 of potentially antagonized the the effect of apoptosis induction, with influence cell metabolism
Summary
Cutaneous squamous cell carcinoma (cSCC), originating from the epidermis or adnexal keratinocytes, is one of the highest incidence of non-melanocytic skin carcinoma, only second to basal cell carcinoma. Because cSCC is a kind of highly metastatic malignant tumors, the death risk of cSCC patients is much higher than the patients with basal cell carcinoma [1]. Improvements in treatment of cSCC could be by means of novel agents targeting the signaling pathways that facilitate cancer cell growth and survival [2]. Flavonoid wogonin is extracted from the traditional Chinese medicine Scutellaria baicalensis with multiple of pharmacological effects, Molecules 2020, 25, 5033; doi:10.3390/molecules25215033 www.mdpi.com/journal/molecules. GL-V9 is derivative from wogonin, which is improved in druggability and shows potent anti-tumor effect in several of cancer cells via inducing apoptosis and cell cycle arrest, as well as inhibiting invasion [5,6,7,8]. The anticancer effects of GL-V9 on cSCC are rarely reported
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