Celastrol upregulated ATG7 triggers autophagy via targeting Nur77 in colorectal cancer

Wenxin Zhang; Zimei Wu; Huijie Qi; Lu Chen; Tianxiao Wang; Xiang Mao; Huanying Shi; Haifei Chen; Mingkang Zhong; Xiaojin Shi; Xinhai Wang; Qunyi Li

doi:10.1016/j.phymed.2022.154280

Celastrol upregulated ATG7 triggers autophagy via targeting Nur77 in colorectal cancer

Phytomedicine. 2022 Sep:104:154280. doi: 10.1016/j.phymed.2022.154280. Epub 2022 Jun 16.

Authors

Wenxin Zhang¹, Zimei Wu¹, Huijie Qi¹, Lu Chen¹, Tianxiao Wang¹, Xiang Mao², Huanying Shi¹, Haifei Chen¹, Mingkang Zhong¹, Xiaojin Shi³, Xinhai Wang⁴, Qunyi Li⁵

Affiliations

¹ Department of Pharmacy, Huashan Hospital, Fudan University, No.12 Urumqi Middle Road, Shanghai 200040, China.
² Department of Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
³ Department of Pharmacy, Huashan Hospital, Fudan University, No.12 Urumqi Middle Road, Shanghai 200040, China. Electronic address: xiaojin_shi@hotmail.com.
⁴ Department of Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: shbg20090109@163.com.
⁵ Department of Pharmacy, Huashan Hospital, Fudan University, No.12 Urumqi Middle Road, Shanghai 200040, China. Electronic address: qyli1234@163.com.

PMID: 35752079
DOI: 10.1016/j.phymed.2022.154280

Abstract

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.

Keywords: ATG7; Autophagy; Celastrol; Colorectal cancer; Nur77.

MeSH terms

Animals
Apoptosis
Autophagy*
Autophagy-Related Protein 7 / metabolism
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms* / pathology
Humans
Mice
Pentacyclic Triterpenes / pharmacology

Substances

Atg7 protein, mouse
Pentacyclic Triterpenes
ATG7 protein, human
Autophagy-Related Protein 7
celastrol