Abstract 2740: The role of JNK in the development of pancreatic cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC C-Jun NH2-terminal kinase (JNK) is a member of mitogen-activated protein kinase (MAPK) family, and it is known to regulate a variety of cellular activities including apoptosis, survival, differentiation, and proliferation. Recently, it has been suggested that JNK is involved in the development of several cancers, but the role of JNK in pancreatic cancer is not fully elucidated. In this study, we examined the role of JNK in the development of pancreatic cancer and evaluated the therapeutic effect of JNK inhibition on pancreatic cancer. In immunohistochemical staining, JNK activation was observed in human pancreatic cancer specimens. Growth of pancreatic cancer cell lines was inhibited by treatment with JNK inhibitor SP600125 or by transfection of siRNAs against JNK1 or JNK2. Expression of cyclin D1 in pancreatic cancer cells was decreased by JNK inhibition, and cell cycle analysis showed accumulation of cells in G0/G1 phase by JNK1 and JNK2 inhibition. Induction of oncogenic Ras into pancreatic cancer cells promoted JNK activation, and KRAS knockdown by siRNA decreased phosphorylation of JNK. Cyclin D1 expression was shown to be regulated through JNK activation by luciferase assay and real-time RT-PCR. Pancreas-specific KrasG12D expression and type II TGFβreceptor knockout mice (KrasG12D+Tgfbr2KO mice) was used as a mouse model of pancreatic cancer, and pancreatic cancer developed in KrasG12D+Tgfbr2KO mice showed higher activation of JNK than PanIN tissue of KrasG12D mice or normal pancreas of wild-type mice. Treating KrasG12D+Tgfbr2KO mice with JNK inhibitor for 4 weeks led to less progression of pancreatic cancer, and immunohistochemical staining showed reduced expression of phosphorylated JNK, c-jun, cyclin D1 and PCNA in the pancreatic cancer tissues compared to control vehicle. The survival time of KrasG12D+Tgfbr2KO mice was significantly prolonged by SP600125 treatment. Decreased number of blood vessels was observed in pancreatic cancer tissue of KrasG12D+Tgfbr2KO mice treated by SP600125. Secretion of angiogenic cytokines from pancreatic cancer cell lines was decreased by JNK inhibition, and angiogenesis by HUVEC was inhibited by incubating in the conditioned medium of pancreatic cancer cells treated by SP600125 or transfected with siRNAs against JNK1 or JNK2, indicating the effect of JNK inhibition on tumor angiogenesis. These data indicate that oncogenic K-ras activates JNK JNK is involved in the development of pancreatic cancer through the regulation of cell cycle and tumor angiogenesis. Inhibiting JNK may be a potential therapy for pancreatic cancer. Citation Format: Ryota Takahashi, Yoshihiro Hirata, Kosuke Sakitani, Wachiko Nakata, Hiroto Kinoshita, Yoku Hayakawa, Hayato Nakagawa, Hideaki Ijichi, Shin Maeda, Kazuhiko Koike. The role of JNK in the development of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2740. doi:10.1158/1538-7445.AM2013-2740