Abstract
Chondrosarcoma is a malignant primary bone tumor. Sirtuin-1 (SIRT1), which is a member of sirtuin family, plays a dual role either in cancer promotion or suppression. There is no report about the role of SIRT1 in the human chondrosarcoma cells. Resveratrol is a potent activator of SIRT1. However, its effects on chondrosarcoma have not been extensively studied. Here, we investigated the role of SIRT1 induction by resveratrol in human chondrosarcoma cell growth and tumor progression. Resveratrol significantly decreased cell viability and induced cell apoptosis in human chondrosarcoma cells in a dose-dependent manner. The protein expression and activity of SIRT1 were activated after treatment with resveratrol. Resveratrol significantly inhibited NF-κB signaling by deacetylating the p65 subunit of NF-κB complex, which could be reversed by siRNA-SIRT1 transfection or deacetylation inhibitor MS-275. Resveratrol induced-apoptosis involved a caspase-3-mediated mechanism. Both siRNA-SIRT1 transfection and MS-275 significantly inhibited the resveratrol-induced caspase-3 cleavage and activity in human chondrosarcoma cells. Moreover, in vivo chondrosarcoma xenograft study revealed a dramatic reduction in tumor volume and the increased SIRT1 and cleaved caspase-3 expressions in tumors by resveratrol treatment. These results suggest that resveratrol induces chondrosarcoma cell apoptosis via a SIRT1-activated NF-κB deacetylation and exhibits anti-chondrosarcoma activity in vivo.
Highlights
Chondrosarcoma is one of the most common primary bone tumors ranking after myeloma and osteosarcoma, accounting for approximately 20% of bone sarcomas and may occur at any age between 10 and 80 years[1]
It has been reported that SIRT1 deacetylates and inactivates hypoxia-inducible factor (HIF)-1α, suppresses the genes expression targeted by HIF-1α in certain tumors[28]
Ex vivo analysis of tumors excised from mice showed significantly increased SIRT1 and cleaved caspase-3 expressions in the resveratrol-treated group compared with that in the control group, as shown by Western blot (Fig. 7) and immunohistochemistry (Fig. 8). These results indicated that resveratrol suppressed the growth of xenograft tumors in Nu/Nu nude mice, and SIRT1 did play a role in resveratrol-induced chondrosarcoma cell apoptosis
Summary
Chondrosarcoma is one of the most common primary bone tumors ranking after myeloma and osteosarcoma, accounting for approximately 20% of bone sarcomas and may occur at any age between 10 and 80 years[1]. There are seven isoforms of sirtuins in mammalian named SIRT1-7, which possess either histone deacetylase (SIRT1-3, SIRT5 and SIRT7) or monoribosyltransferase activity (SIRT4 and SIRT6)[23]. They are participated in a wide range of cellular processes and pathways with different cellular localization and molecular targets. It has been reported that SIRT1 deacetylates and inactivates hypoxia-inducible factor (HIF)-1α, suppresses the genes expression targeted by HIF-1α in certain tumors[28]. We tried to evaluate the therapeutic effects of resveratrol via SIRT1 activation on chondrosarcoma cell growth and tumor progression using an in vitro cell culture model and an in vivo xenograft mouse model
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