TGF-β1 Facilitates TAp63α Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration
TGF-β signaling plays a pivotal role in promoting tumor cell migration and cancer metastasis. ΔNp63α and TAp63α are two major isoforms of p53-related p63 protein. Our recent study has shown that TGF-β1 promotes ΔNp63α protein degradation to facilitate cancer metastasis. However, whether TAp63α is in...
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doaj-0e858eb5554d492688789bd542a254532021-07-23T13:31:05ZengMDPI AGBiology2079-77372021-06-011059759710.3390/biology10070597TGF-β1 Facilitates TAp63α Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell MigrationGuohui Gao0Jie Chen1Dongbo Wang2Qiao Li3Xiaojiao Yang4Jindan Wang5Zhiyong Pan6Zhi-Xiong Jim Xiao7Yong Yi8Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, ChinaThe First Clinical College, Wenzhou Medical University, Wenzhou 325000, ChinaCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, ChinaThe First Clinical College, Wenzhou Medical University, Wenzhou 325000, ChinaSchool of Pharmacy, Wenzhou Medical University, Wenzhou 325000, China Key Laboratory of Laboratory Medicine, School of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, Wenzhou 325000, China Key Laboratory of Laboratory Medicine, School of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, Wenzhou 325000, ChinaCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, ChinaCenter of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, ChinaTGF-β signaling plays a pivotal role in promoting tumor cell migration and cancer metastasis. ΔNp63α and TAp63α are two major isoforms of p53-related p63 protein. Our recent study has shown that TGF-β1 promotes ΔNp63α protein degradation to facilitate cancer metastasis. However, whether TAp63α is involved in TGF-β1-induced cancer metastasis remains unclear. In this study, we show that, in human pancreatic cancer MIA PaCa-2 cells harboring p53-R248W allele, TGF-β1 can significantly inhibit TAp63α protein stability in a Smad pathway-independent manner. Lysosome inhibitor, chloroquine, but not proteasome inhibitor MG132, can rescue TGF-β1-induced downregulation of TAp63α protein. In addition, we show that either TGF-β1 treatment or silencing of TAp63α can dramatically increase migration of MIA PaCa-2 cells. Importantly, the restored expression of TAp63α can effectively block TGF-β1-induced migration of MIA PaCa-2 cells. Mechanistically, we show that TGF-β1 promotes TAp63α 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 TAp63α protein fate and highlights that TGF-β1-TAp63α-mutant p53 axis is critically important in pancreatic cancer metastasis.https://www.mdpi.com/2079-7737/10/7/597TGF-β1TAp63αp53cell migrationpancreatic cancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Guohui Gao Jie Chen Dongbo Wang Qiao Li Xiaojiao Yang Jindan Wang Zhiyong Pan Zhi-Xiong Jim Xiao Yong Yi |
spellingShingle |
Guohui Gao Jie Chen Dongbo Wang Qiao Li Xiaojiao Yang Jindan Wang Zhiyong Pan Zhi-Xiong Jim Xiao Yong Yi TGF-β1 Facilitates TAp63α Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration Biology TGF-β1 TAp63α p53 cell migration pancreatic cancer |
author_facet |
Guohui Gao Jie Chen Dongbo Wang Qiao Li Xiaojiao Yang Jindan Wang Zhiyong Pan Zhi-Xiong Jim Xiao Yong Yi |
author_sort |
Guohui Gao |
title |
TGF-β1 Facilitates TAp63α Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration |
title_short |
TGF-β1 Facilitates TAp63α Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration |
title_full |
TGF-β1 Facilitates TAp63α Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration |
title_fullStr |
TGF-β1 Facilitates TAp63α Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration |
title_full_unstemmed |
TGF-β1 Facilitates TAp63α Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration |
title_sort |
tgf-β1 facilitates tap63α protein lysosomal degradation to promote pancreatic cancer cell migration |
publisher |
MDPI AG |
series |
Biology |
issn |
2079-7737 |
publishDate |
2021-06-01 |
description |
TGF-β signaling plays a pivotal role in promoting tumor cell migration and cancer metastasis. ΔNp63α and TAp63α are two major isoforms of p53-related p63 protein. Our recent study has shown that TGF-β1 promotes ΔNp63α protein degradation to facilitate cancer metastasis. However, whether TAp63α is involved in TGF-β1-induced cancer metastasis remains unclear. In this study, we show that, in human pancreatic cancer MIA PaCa-2 cells harboring p53-R248W allele, TGF-β1 can significantly inhibit TAp63α protein stability in a Smad pathway-independent manner. Lysosome inhibitor, chloroquine, but not proteasome inhibitor MG132, can rescue TGF-β1-induced downregulation of TAp63α protein. In addition, we show that either TGF-β1 treatment or silencing of TAp63α can dramatically increase migration of MIA PaCa-2 cells. Importantly, the restored expression of TAp63α can effectively block TGF-β1-induced migration of MIA PaCa-2 cells. Mechanistically, we show that TGF-β1 promotes TAp63α 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 TAp63α protein fate and highlights that TGF-β1-TAp63α-mutant p53 axis is critically important in pancreatic cancer metastasis. |
topic |
TGF-β1 TAp63α p53 cell migration pancreatic cancer |
url |
https://www.mdpi.com/2079-7737/10/7/597 |
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