Background

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.

Purpose

The main purpose was to investigate the anti-CRC effects of celastrol and its novel potential mechanisms.

Study design

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.

Methods

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.

Results

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.

Conclusion

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.

中文翻译：

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Celastrol通过靶向结直肠癌中的Nur77上调ATG7触发自噬

背景

Celastrol 是一种从雷公藤中提取的生物活性成分，具有抗癌特性。我们在本研究中探讨了 celastrol 对结直肠癌 (CRC) 的抗肿瘤活性以及参与其机制的潜在信号通路。

目的

主要目的是研究 celastrol 的抗 CRC 作用及其新的潜在机制。

学习规划

HCT-116和SW480细胞系用于体外研究，CRC肿瘤的小鼠异种移植模型进行体内研究。

方法

通过使用蛋白质印迹分析、细胞增殖测定、PI 和膜联蛋白-V 染色测定、免疫荧光和 qRT-PCR 测定，检查了 celastrol 对体外结直肠癌细胞的影响和潜在机制。CRC异种移植模型和IHC染色主要用于评估celastrol在体内的作用。

结果

结果表明，celastrol 可诱导 CRC 细胞凋亡并抑制其增殖。Nur77 的表达影响 celastrol 的抗 CRC 作用，并且 celastrol 对 CRC 细胞的抑制作用可以通过过表达 Nur77 来逆转。Celastrol 诱导自噬和自噬抑制增强了抗 CRC 作用。在 celastrol 处理过表达 Nur77 的 CRC 癌细胞后，ATG7 明显上调。用 celastrol 治疗植入 CRC 细胞的小鼠表明它有效地抑制了肿瘤生长，这与 Nur77 的下调有关。Nur77 和 ATG7 的水平与人类结直肠癌的存活率相关。

结论

Celastrol诱导细胞凋亡和自噬在人结直肠癌中起重要作用，Nur77参与了celastrol的抗CRC作用，降低Nur77表达诱导ATG7高表达。Celastrol 通过抑制 Nur77 诱导 ATG7 信号的高表达发挥抗 CRC 作用，Nur77/ATG7 信号可能是治疗结直肠癌的潜在途径。