Abstract PO-093: JNK2 suppresses the growth and invasion of pancreatic cancer and is opposed by JNK1

Abstract

Abstract Introduction: Pancreatic cancer cells are exposed to multiple stressors with both endogenous (proliferation, metabolism and nutrient deprivation) and exogenous (medical treatment) origins. The c-Jun N-terminal protein kinases (JNKs) JNK1 and JNK2 are important stress-activated kinases, responsible for the cellular response to these stressors. Both were demonstrated to exert both tumor-suppressing and tumor-promoting effects in human cancers Most previous studies rely on nonspecific pharmacological JNK inhibition. In this study, we planned to determine the isoform-specific roles in PDAC. Methods: Specific JNK1- and JNK2-knockdown (KD) clones were established in cultured human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 by using specific shRNA plasmids. Anchorage dependent and independent growth, as well as migration and invasion, were analyzed in JNK-1/2 KD clones and compared to pharmacological JNK inhibition using SP600125. Xenograft growth was assessed using an orthotopic mouse model. Mechanistically, we assessed changes in EMT markers both in vitro and in vivo. Results: JNKs were expressed in both cultured pancreatic cancer cell lines as well as in resected human pancreatic cancer samples. Specific downregulation of JNK2 resulted in an overall increase in cell proliferation, invasion and alterations in cytoskeleton structure, while JNK1-KD revealed opposite effects. Nonspecific JNK-inhibition using SP600125 inhibited cell growth of all cell lines except PANC-1. Conclusion: JNK1 and JNK2 play opposing roles in human pancreatic cancer. Specifically targeting JNK1 with the retained function of JNK2 may provide a potential, individualized approach for targeting pancreatic cancer progression. Citation Format: Jingwei Shi, Xiaodong Tian, Marko Kornmann, Benno Traub. JNK2 suppresses the growth and invasion of pancreatic cancer and is opposed by JNK1 [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-093.