Degalactotigonin Exerts Effective Inhibition on the Growth, Metastasis and Sunitinib-Resistance of Renal Cell Carcinoma Through Inactivating YAP Signaling

Background: The pervasive progression and drug-resistance of renal cell carcinoma (RCC) after treatments demands for more effective drugs with little side effects. Recently, extracts from natural resources have been reported to effectively suppress the progression of certain tumors. In this study, we examined the effects of degalactotigonin extracted from Solanum nigrum L. on the progression and sunitinib-resistance of RCC, and the underlying mechanisms. Methods: The in vitro effects of degalactotigonin on the proliferation, apoptosis, invasion, migration and sunitinib-resistance were assessed by CCK-8, flow cytometry, Western blot, Matrigel invasion and transwell migration assays. The in vivo effects were evaluated in murine models of subcutaneous and in situ tumor and lung metastasis. The related molecular characteristics were delineated by RNA-sequencing. Findings: Degalactotigonin induced apoptosis and suppressed proliferation, invasion, migration, and sunitinib-resistance of RCC cells in vitro in a dose-dependent manner. Furthermore, degalactotigonin effectively inhibited the tumorigenicity and lung metastasis of RCC cells in vivo. Mechanistically, RNA-sequencing revealed that inactivation of YAP signaling occurred in degalactotigonin-treated RCC cells with reduced expression of YAP and its target genes. We also observed that degalactotigonin activated p-LATS1/2 to phosphorylate YAP, which induced more YAP retention in the cytoplasm but less YAP entering the nucleus of RCC cells. Moreover, re-expressed YAP in degalactotigonin-treated RCC cells mediated the anti-tumor activities of degalactotigonin on RCC. Furthermore, degalactotigonin ameliorated sunitinib-resistance in an orthotopic RCC model. Interpretation: Degalactotigonin is an effective therapeutic agent in inhibiting the growth, progression and sunitinib-resistance of RCC. Funding Statement: National Natural Science Foundation of China (No. 81773154, 81772747 and 81301861), Shanghai Natural Science Foundation of China (No. 13ZR1450700), the Shanghai Medical Guidance (Chinese and Western Medicine) Science and Technology Support Project (No. 17411960200). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: All experimental animal procedures were approved by the Animal Care and Use Committee of the Second Military Medical University (Shanghai, China).