C-Jun N-terminal kinase 2 suppresses pancreatic cancer growth and invasion and is opposed by c-Jun N-terminal kinase 1

Xiaodong Tian,Benno Traub,Doris Henne-Bruns,Jingwei Shi,Uwe Knippschild,Guowei Chen,Stefan Schreiner,Shaoxia Zhou,Marko Kornmann,Nadine Huber

doi:10.1038/s41417-020-00290-5

Abstract

The c-Jun N-terminal protein kinases (JNKs) JNK1 and JNK2 can act as either tumor suppressors or pro-oncogenic kinases in human cancers. The isoform-specific roles for JNK1 and JNK2 in human pancreatic cancer are still unclear, the question which should be addressed in this project. Human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 clones were established either expressing either JNK1 or -2 shRNA in a stable manner. Basal anchorage-dependent and –independent cell growth, single-cell movement, and invasion using the Boyden chamber assay were analyzed. Xenograft growth was assessed using an orthotopic mouse model. All seven tested pancreatic cancer cell lines expressed JNKs as did human pancreatic cancer samples determined by immunohistochemistry. Pharmacological, unspecific JNK inhibition (SP600125) reduced cell growth of all cell lines but PANC-1. Especially inhibition of JNK2 resulted in overall increased oncogenic potential with increased proliferation and invasion, associated with alterations in cytoskeleton structure. Specific inhibition of JNK1 revealed opposing functions. Overall, JNK1 and JNK2 can exert different functions in human pancreatic cancer and act as counter players for tumor invasion. Specifically modulating the activity of JNKs may be of potential therapeutic interest in the future.

Highlights

Human pancreatic cancer is an aggressive and devastating malignancy with a poor prognosis
Jun N-terminal protein kinases (JNKs) play important roles in mediating several biological functions involved in altering the malignant phenotype of cancer cells via modulation of the Ras-pathway and p53 functions [5, 8]
Human pancreatic cancer is a devastating disease characterized by strong local invasion, stromal fibrosis, local recurrence, and metastases and frequently harboring Ras- and p53-mutations [4]

Summary

Introduction

Human pancreatic cancer is an aggressive and devastating malignancy with a poor prognosis. The c-Jun N-terminal protein kinases (JNKs), which were referred to as stress-activated kinases (SAPKs) for. These authors contributed : Xiaodong Tian, Benno Traub. JNKs have been recognized as critical regulators for several physiological functions like cell proliferation, apoptosis, DNA repair, and metabolism. The variety of different physiologic functions is addressed by multiple downstream substrates, among those c-Jun, ATF-2, and p53 Within this complexity, there is still room for opposing functions like inducing apoptosis as well as enhancement of cell survival and proliferation [8, 9]

Objectives

Methods

Conclusion