Department of Pharmacy, Huashan Hospital, Fudan University, No.12 Urumqi Middle Road, Shanghai 200040, China.
Department of Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
Phytomedicine. 2022 Sep;104:154280. doi: 10.1016/j.phymed.2022.154280. Epub 2022 Jun 16.
Celastrol is a biologically active ingredient extracted from Tripterygium wilfordii that has exerted properties of anti-cancer. We explored the anti-tumor activities of celastrol against colorectal cancer (CRC) and the potential signaling pathways involved in its mechanism in this study.
The main purpose was to investigate the anti-CRC effects of celastrol and its novel potential mechanisms.
HCT-116 and SW480 cell lines were used for in vitro studies, the mouse xenograft model of CRC tumor was performed for in vivo studies.
The effects of celastrol on colorectal cancer cells in vitro and underlying mechanisms were examined by using western blot analysis, cell proliferation assays, PI and Annexin-V staining assays, immunofluorescence and qRT-PCR assay. CRC xenografts model and IHC-staining were mainly used to evaluate the effects of celastrol in vivo.
The results demonstrated that celastrol induced apoptosis and inhibited proliferation in CRC cells. The expression of Nur77 influenced the anti-CRC effects of celastrol, and inhibitory effect of celastrol on CRC cells could be reversed by overexpressing Nur77. Celastrol induced autophagy and the autophagy inhibition enhanced the anti-CRC effects. The ATG7 was up-regulated obviously after celastrol treatment for Nur77 overexpressing CRC cancer cells. Treating mice implanted with CRC cells with celastrol showed that it effectively inhibited tumor growth, which was associated with the down-regulation of Nur77. Levels of Nur77 and ATG7 were correlated with survival in human colorectal cancer.
Celastrol induced apoptosis and autophagy played an important role in human colorectal cancer, Nur77 was involved in the anti-CRC effect of celastrol and decreased expression of Nur77 induced high expression of ATG7. Celastrol exerted anti-CRC effects by inhibiting Nur77 to induce high expression of ATG7 signaling and Nur77/ATG7 signaling may be a potential pathway for colorectal cancer treatment.
从雷公藤中提取的生物活性成分雷公藤红素具有抗癌作用。本研究旨在探讨雷公藤红素对结直肠癌（CRC）的抗肿瘤活性及其作用机制中的潜在信号通路。
主要目的是研究雷公藤红素对 CRC 的抑制作用及其潜在的新机制。
采用 HCT-116 和 SW480 细胞系进行体外研究，建立 CRC 肿瘤小鼠异种移植模型进行体内研究。
采用 Western blot 分析、细胞增殖试验、PI 和 Annexin-V 染色试验、免疫荧光和 qRT-PCR 检测等方法研究雷公藤红素对结直肠癌细胞的作用及其机制。CRC 异种移植模型和免疫组化染色主要用于评估雷公藤红素在体内的作用。
结果表明，雷公藤红素诱导 CRC 细胞凋亡并抑制增殖。Nur77 的表达影响雷公藤红素的抗 CRC 作用，过表达 Nur77 可逆转雷公藤红素对 CRC 细胞的抑制作用。雷公藤红素诱导自噬，自噬抑制增强了抗 CRC 作用。雷公藤红素处理过表达 Nur77 的 CRC 癌细胞后，ATG7 明显上调。用雷公藤红素处理荷 CRC 细胞的小鼠，发现其能有效抑制肿瘤生长，这与 Nur77 的下调有关。Nur77 和 ATG7 的水平与人类结直肠癌的生存相关。
雷公藤红素诱导的凋亡和自噬在人结直肠癌中起重要作用，Nur77 参与了雷公藤红素的抗 CRC 作用，Nur77 表达下调诱导 ATG7 高表达。雷公藤红素通过抑制 Nur77 诱导 ATG7 信号高表达发挥抗 CRC 作用，Nur77/ATG7 信号可能是结直肠癌治疗的潜在途径。
