Autophagic flux is essential for the downregulation of D-dopachrome tautomerase by atractylenolide I to ameliorate intestinal adenoma formation
Autor: | Jun-Jiang Wang, Ye Ma, Xuegang Sun, Lu Li, Yiye Zhao, Wenjuan Xu, Linlin Jing, Xueqing Yao, Xianling Gong |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Gene knockdown Adenoma biology Adenomatous polyposis coli Chemistry Autophagy Cellular homeostasis Cell Biology Colorectal adenoma medicine.disease Biochemistry Familial adenomatous polyposis 03 medical and health sciences 030104 developmental biology Downregulation and upregulation Cancer research medicine biology.protein Molecular Biology Research Article |
Zdroj: | Journal of Cell Communication and Signaling. 12:689-698 |
ISSN: | 1873-961X 1873-9601 |
DOI: | 10.1007/s12079-018-0454-6 |
Popis: | Colorectal cancer is generally believed to progress through an adenoma - carcinoma sequence. Adenomatous polyposis coli (APC) mutations serve as the initiating event in adenoma formation. The ApcMin/+ mouse harbors a mutation in the APC gene, which is similar or identical to the mutation found in individuals with familial adenomatous polyposis and 70% of all sporadic CRC cases. Autophagy is a constitutive process required for proper cellular homeostasis. However, its role in intestinal adenoma formation is still controversial. Atractylenolide I (AT1) is a sesquiterpenoid that possesses various clinically relevant properties such as anti-tumor and anti-inflammatory activities. The role of AT1 on adenoma formation was tested in ApcMin/+ mice and its underlying mechanism in regulating autophagy was documented. D-dopachrome tautomerase (D-DT) was identified as a potential target of AT1 by an proteomics-based approach. The effects of p53 modification on autophgic flux was monitored in p53−/− and p53+/+ HCT116 cells. Small interfering RNA was used to investigate the function of Atg7 and D-DT on autophagy programme induce by AT1. AT1 effectively reduced the formation of adenoma and downregulated the tumorigenic proteins in ApcMin/+ mice. Importantly, AT1 stimulated autophagic flux through downregulating acetylation of p53. Activation of Sirt1 by AT1 was essential for the deacetylation of p53 and downregulation of D-DT. The lowered expression of COX-2 and β-catenin by AT1 were partly recovered by Atg7 knockdown. AT1 activates autophagy machinery to downregulate D-DT and reduce intestinal adenoma formation. This discovery provides evidence in vivo and in vitro that inducing autophagy by natural products maybe a potential therapy to ameliorate colorectal adenoma formation. |
Databáze: | OpenAIRE |
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