TGF-beta 1 Facilitates TAp63 alpha Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration

doi:10.3390/biology10070597

科研成果详情

题名	TGF-beta 1 Facilitates TAp63 alpha Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration
作者	Gao, Guohui1,2; Chen, Jie 3; Wang, Dongbo 1; Li, Qiao 3; Yang, Xiaojiao4; Wang, Jindan2; Pan, Zhiyong2; Xiao, Zhi-Xiong Jim 1; Yi, Yong 1
发表日期	2021-07
发表期刊	BIOLOGY-BASEL 影响因子和分区
语种	英语
原始文献类型	Article
关键词	TGF-beta 1 TAp63 alpha p53 cell migration pancreatic cancer
其他关键词	GERM-LINE ; BETA ; P63 ; METASTASIS ; DELTA-NP63-ALPHA ; EXPRESSION ; PATHWAYS ; INVASION
摘要	Simple Summary Numerous studies demonstrate that the activation of transforming growth factor-beta (TGF-beta) signaling is a critical driving force for promoting cancer cell migration and tumor metastasis. Our recent study indicates that TGF-beta 1 promotes FBXO3-mediated Delta Np63 alpha protein degradation to facilitate cancer metastasis. In this study, we show that TGF-beta 1 can inhibit TAp63 alpha protein stability in a lysosome-dependent, but canonical Smad pathway-independent manner, which leads to upregulation of p53-R248W expression, and consequently results in increased pancreatic cancer cell migration. TGF-beta signaling plays a pivotal role in promoting tumor cell migration and cancer metastasis. Delta Np63 alpha and TAp63 alpha are two major isoforms of p53-related p63 protein. Our recent study has shown that TGF-beta 1 promotes Delta Np63 alpha protein degradation to facilitate cancer metastasis. However, whether TAp63 alpha is involved in TGF-beta 1-induced cancer metastasis remains unclear. In this study, we show that, in human pancreatic cancer MIA PaCa-2 cells harboring p53-R248W allele, TGF-beta 1 can significantly inhibit TAp63 alpha protein stability in a Smad pathway-independent manner. Lysosome inhibitor, chloroquine, but not proteasome inhibitor MG132, can rescue TGF-beta 1-induced downregulation of TAp63 alpha protein. In addition, we show that either TGF-beta 1 treatment or silencing of TAp63 alpha can dramatically increase migration of MIA PaCa-2 cells. Importantly, the restored expression of TAp63 alpha can effectively block TGF-beta 1-induced migration of MIA PaCa-2 cells. Mechanistically, we show that TGF-beta 1 promotes TAp63 alpha protein degradation, leading to upregulation of p53-R248W protein expression, and consequently resulting in elevated MIA PaCa-2 cell migration. Together, this study indicates that lysosomal degradation is an important way for regulating TAp63 alpha protein fate and highlights that TGF-beta 1-TAp63 alpha-mutant p53 axis is critically important in pancreatic cancer metastasis.
资助项目	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [82073248, 81802951, 81861148031]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2020T130451, 2018M631081]; Zhejiang Provincial Key Discipline of Medical Science Foundation [437202002]
出版者	MDPI
出版地	BASEL
ISSN	2079-7737
EISSN	2079-7737
卷号	10 期号:7 页码:597
DOI	10.3390/biology10070597
页数	10
WOS类目	Biology
WOS研究方向	Life Sciences & Biomedicine - Other Topics
WOS记录号	WOS:000675924500001
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	34203341
PMC记录号	PMC8301043
SCOPUSEID	2-s2.0-85109673042
通讯作者地址	[Yi, Yong]Center of Growth,Metabolism and Aging,Key Laboratory of Bio-Resource and Eco-Environment,Ministry of Education,College of Life Sciences,Sichuan University,Chengdu,610064,China
Scopus学科分类	Biochemistry, Genetics and Molecular Biology (all);Immunology and Microbiology (all);Agricultural and Biological Sciences (all)
引用统计	被引频次：2[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/16750
专题	检验医学院（生命科学学院、生物学实验教学中心）药学院（分析测试中心）第一临床医学院（信息与工程学院）、附属第一医院
通讯作者	Yi, Yong
作者单位	1.Center of Growth,Metabolism and Aging,Key Laboratory of Bio-Resource and Eco-Environment,Ministry of Education,College of Life Sciences,Sichuan University,Chengdu,610064,China; 2.Key Laboratory of Laboratory Medicine,School of Laboratory Medicine,Ministry of Education,Wenzhou Medical University,Wenzhou,325000,China; 3.The First Clinical College,Wenzhou Medical University,Wenzhou,325000,China; 4.School of Pharmacy,Wenzhou Medical University,Wenzhou,325000,China
第一作者单位	检验医学院（生命科学学院、生物学实验教学中心）
推荐引用方式 GB/T 7714	Gao, Guohui,Chen, Jie,Wang, Dongbo,et al. TGF-beta 1 Facilitates TAp63 alpha Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration[J]. BIOLOGY-BASEL,2021,10(7):597.
APA	Gao, Guohui., Chen, Jie., Wang, Dongbo., Li, Qiao., Yang, Xiaojiao., ... & Yi, Yong. (2021). TGF-beta 1 Facilitates TAp63 alpha Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration. BIOLOGY-BASEL, 10(7), 597.
MLA	Gao, Guohui,et al."TGF-beta 1 Facilitates TAp63 alpha Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration".BIOLOGY-BASEL 10.7(2021):597.