Intracellular complement C5a/C5aR1 stabilizes β-catenin to promote colorectal tumorigenesis

Peipei Ding; Yanqing Xu; Luying Li; Xinyue Lv; Ling Li; Jianfeng Chen; Danlei Zhou; Xiaochao Wang; Qi Wang; Wei Zhang; Tian Liao; Qing-Hai Ji; Qun-Ying Lei; Weiguo Hu

doi:10.1016/j.celrep.2022.110851

Intracellular complement C5a/C5aR1 stabilizes β-catenin to promote colorectal tumorigenesis

Cell Rep. 2022 May 31;39(9):110851. doi: 10.1016/j.celrep.2022.110851.

Authors

Peipei Ding¹, Yanqing Xu¹, Luying Li¹, Xinyue Lv¹, Ling Li¹, Jianfeng Chen¹, Danlei Zhou¹, Xiaochao Wang¹, Qi Wang¹, Wei Zhang¹, Tian Liao², Qing-Hai Ji², Qun-Ying Lei³, Weiguo Hu⁴

Affiliations

¹ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
² Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
³ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.
⁴ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China. Electronic address: weiguohu@fudan.edu.cn.

PMID: 35649359
DOI: 10.1016/j.celrep.2022.110851

Abstract

Complement is operative in not only the extracellular but also the intracellular milieu. However, little is known about the role of complement activation inside tumor cells. Here, we report that intracellular C5 is cleaved by cathepsin D (CTSD) to produce C5a in lysosomes and endosomes of colonic cancer cells. After stimulation by C5a, intracellular C5aR1 assembles a complex with KCTD5/cullin3/Roc-1 and β-catenin to promote the switch of polyubiquitination of β-catenin from K48 to K63, which enhances β-catenin stability. Genetic loss or pharmacological blockade of C5aR1 dramatically impedes colorectal tumorigenesis at least by destabilizing β-catenin. In human colorectal cancer specimens, high levels of C5aR1, C5a, and CTSD are closely correlated with elevated β-catenin levels and a poor prognosis. Importantly, intracellular C5a/C5aR1-mediated β-catenin stabilization is also observed ubiquitously in other cell types. Collectively, we identify a machinery for β-catenin activation and provide a potential target for tumor prevention and treatment.

Keywords: C5a; C5aR1; CP: cancer; cathepsin D; colorectal cancer; β-catenin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis
Colorectal Neoplasms*
Complement Activation
Complement C5a* / metabolism
Humans
Potassium Channels
beta Catenin / metabolism

Substances

KCTD5 protein, human
Potassium Channels
beta Catenin
Complement C5a