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γ-Synuclein is Closely Involved in Autophagy that Protects Colon Cancer Cell from Endoplasmic Reticulum Stress

[ Vol. 21 , Issue. 17 ]

Author(s):

Qing Ye, Yuanfei Peng, Feng Huang*, Jinhu Chen, Yangmei Xu, Yangming Li, Shengyuan Liu and Lijie Huang   Pages 2385 - 2396 ( 12 )

Abstract:


Background: In previous studies, we provided evidence suggesting the involvement of γ-synuclein in growth, invasion, and metastasis of colon cancer cells in vitro and in vivo. Among γ-synuclein downstream genes, the microtubule-associated protein 1 Light Chain 3 (LC3), an autophagy gene, was screened by gene expression profile chip analysis.

Objective: We planned to investigate the functional effects of γ-synuclein on autophagy induced by ER stress in colon cancer cells.

Methods: We investigated the functional effects of γ-synuclein on autophagy and apoptosis induced by Thapsigargin (TG), ER stress-inducing agent, in colon cancer cell lines using immunofluorescence staining, RT-PCR, western blot, CCK8 test, flow cytometry analysis, and transmission electron microscopy. To further determine how γ-synuclein regulated autophagy and apoptosis, PD98059 (ERK inhibitor), SP600125 (ERK inhibitor), anisomycin (JNK activator), and c-Jun siRNA were used respectively in γ-synuclein siRNA transfected HCT116 cells. Then, autophagy proteins, apoptosis proteins, and pathway proteins were detected by western blot analysis. The expression of autophagy genes was assessed by RT-PCR.

Results: Our data showed that ER stress-induced colon cancer cells autophagy mainly in the early stage (0-24h) and apoptosis mainly in the late stage (24-48h). ER stress up-regulated γ-synuclein gene and protein expression in colon cancer cells, accompanied by autophagy. γ-synuclein protected HCT116 cells by enhancing autophagy in the early stage (0-24h) through activation of ERK and JNK pathway and inhibiting apoptosis in the late stage (24-48h) through inhibition of the JNK pathway. γ-synuclein could promote autophagy via the JNK pathway activation of ATG genes, LC3, Beclin 1, and ATG7. γ-synuclein may play a role in the transition between autophagy and apoptosis in our model.

Conclusion: Overall, we provided the first experimental evidence to show that γ-synuclein may play an important role in autophagy that protects colon cancer cells from ER stress. Therefore, our data suggest a new molecular mechanism for γ-synuclein-mediated CRC progression.

Keywords:

γ-synuclein, colon cancer cell, ER stress, autophagy, apoptosis, LC3.

Affiliation:

Department of Gastrointestinal Tumor Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fujian Province Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian Province, 350014, Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, 200032, Department of Gastrointestinal Tumor Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fujian Province Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian Province, 350014, Department of Gastrointestinal Tumor Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fujian Province Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian Province, 350014, Department of Gastrointestinal Tumor Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fujian Province Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian Province, 350014, Department of Gastrointestinal Tumor Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fujian Province Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian Province, 350014, Department of Gastrointestinal Tumor Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fujian Province Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian Province, 350014, Department of Gastrointestinal Tumor Surgery, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fujian Province Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian Province, 350014



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