Alessio Lepore1, Pui Man Choy2, Nathan C W Lee1, Maria Annunziata Carella3, Rosy Favicchio4, Marco A Briones-Orta2,5, Shannon S Glaser6, Gianfranco Alpini7, Clive D'Santos8, Reuben M Tooze1, Mihaela Lorger1, Wing-Kin Syn2,9,10,11, Athanasios Papakyriakou12, Georgios Giamas13, Concetta Bubici3, Salvatore Papa1,2. 1. Leeds Institute of Medical Research at St. James', Faculty of Medicine and Health, University of Leeds, St. James' University Hospital, Leeds, United Kingdom. 2. Institute of Hepatology, Foundation for Liver Research and Birkbeck University of London, London, United Kingdom. 3. Center for Genome Engineering and Maintenance, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, United Kingdom. 4. Department of Surgery and Cancer, Imperial College, London, United Kingdom. 5. Department of Infectious Disease, Imperial College, London, United Kingdom. 6. Department of Medical Physiology, Texas A&M University, Bryan, TX. 7. Division of Gastroenterology, Department of Medicine, Richard L. Roudebush VA Medical Center, Indiana University, Indianapolis, IN. 8. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. 9. Section of Gastroenterology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC. 10. Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC. 11. Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country UPV/EHU, Leioa, Spain. 12. Institute of Biosciences and Applications, National Center for Scientific Research, Athens, Greece. 13. Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, United Kingdom.
Abstract
BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of the 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 therefore 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 signaling in ICC that could open up therapeutic opportunities. APPROACH AND RESULTS: Using loss-of-function 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 tumors, 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 through all-trans retinoic acid, a Food and Drug Administration-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 through PIN1 inhibition.
BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of the 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 therefore 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 signaling in ICC that could open up therapeutic opportunities. APPROACH AND RESULTS: Using loss-of-function 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 tumors, 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 through all-trans retinoic acid, a Food and Drug Administration-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 through PIN1 inhibition.