Abstract
Simple SummaryNumerous studies demonstrate that the activation of transforming growth factor-β (TGF-β) signaling is a critical driving force for promoting cancer cell migration and tumor metastasis. Our recent study indicates that TGF-β1 promotes FBXO3-mediated ΔNp63α protein degradation to facilitate cancer metastasis. In this study, we show that TGF-β1 can inhibit TAp63α 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-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.
Highlights
TGF-β1 is a member of the TGF-β family which plays a pivotal role in a series of biological processes, including cell differentiation, proliferation, epithelial-mesenchymal transition (EMT), cell migration, tumor metastasis and immune escape [1,2,3]
We show that TGF-β1 can significantly inhibit TAp63α protein stability in a lysosome-dependent manner, which leads to the upregulation of p53-R248W protein expression, and results in increased MIA PaCa-2 cell migration
These results demonstrate that TGF-β1 promotes TAp63α protein lysosomal degradation in a canonical Smad-independent manner in MIA PaCa-2 cells
Summary
TGF-β1 is a member of the TGF-β family which plays a pivotal role in a series of biological processes, including cell differentiation, proliferation, epithelial-mesenchymal transition (EMT), cell migration, tumor metastasis and immune escape [1,2,3]. As a ligand for TGF-β receptor, TGF-β1 binds to the TGF-β receptor and transduce signals through canonical Smad pathway or noncanonical Ras–Erk, PI3K/AKT and Rho-like GTPase pathways [4,5]. In the canonical Smad pathway, activated TGF-β receptor phosphorylates. Smad2/Smad, which bind to Smad to form heteromeric Smad complexes translocated into the nucleus to transactivate downstream target genes [4,6,7]. Accumulating evidence indicates that TGF-β1 signaling can execute its function through the regulation of protein stability. It is reported that TGF-β1 can promote iNOS protein degradation in a ubiquitin-proteasome-dependent manner during inflammatory process [8]. TGF-β1 can promote type I collagen protein lysosomal degradation [9]. TGF-β1 can facilitate MyD88 protein degradation by recruiting Smurf and Smurf2 [10]
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