IRUS Total

Phosphorylation and stabilization of PIN1 by JNK promote intrahepatic cholangiocarcinoma growth

File Description SizeFormat 
hep.31983.pdfPublished version1.4 MBAdobe PDFView/Open
Title: Phosphorylation and stabilization of PIN1 by JNK promote intrahepatic cholangiocarcinoma growth
Authors: Lepore, A
Choy, PM
Lee, NC
Carella, MA
Favicchio, R
Briones-Orta, MA
Glaser, SS
Alpini, G
D'Santos, C
Tooze, RM
Lorger, M
Syn, W-K
Papakyriakou, A
Giamas, G
Bubici, C
Papa, S
Item Type: Journal Article
Abstract: BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of c-Jun N-terminal kinase (JNK) pathway is a key feature in ICC and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes ICC growth, and thus the key downstream effectors of this pathway remain unknown for their applicability as therapeutic targets. Our aim was to obtain a better mechanistic understanding of the role of JNK signalling in ICC that could open new therapeutic opportunities. APPROACH AND RESULTS: Using loss- and gain-of-function studies in vitro and in vivo, we show that activation of the JNK pathway promotes ICC cell proliferation by affecting the protein stability of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), a key driver of tumorigenesis. PIN1 is highly expressed in ICC primary tumours, and its expression positively correlates with active JNK. Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. Moreover, pharmacological inhibition of PIN1 via all-trans retinoic acid (ATRA), an FDA-approved drug, impairs the growth of both cultured and xenografted ICC cells. CONCLUSIONS: Our findings implicate the JNK-PIN1 regulatory axis as a functionally important determinant for ICC growth, and provide a rationale for therapeutic targeting of JNK activation via PIN1 inhibition.
Issue Date: 1-Nov-2021
Date of Acceptance: 28-May-2021
URI: http://hdl.handle.net/10044/1/90171
DOI: 10.1002/hep.31983
ISSN: 0270-9139
Publisher: Wiley
Start Page: 2561
End Page: 2579
Journal / Book Title: Hepatology
Volume: 74
Issue: 5
Copyright Statement: This article is protected by copyright. All rights reserved.
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
bile duct cancer
post-translational modification
1101 Medical Biochemistry and Metabolomics
1103 Clinical Sciences
1107 Immunology
Gastroenterology & Hepatology
Publication Status: Published
Conference Place: United States
Open Access location: https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.31983
Online Publication Date: 2021-05-28
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Department of Infectious Diseases
Faculty of Medicine