PKCι and YAP1 are crucial in promoting pancreatic tumorigenesis
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Peipei Wang1, Dapeng Wei1, Hongmei Zhang1, Jiao Chen2, Dingding Zhang3, Suthakar Ganapathy4, Pauline Isakson5, Changyan Chen4 and Tongbo Zhu1
1Department of Immunology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P. R. China
2State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P. R. China
3Sichuan Provincial Key Laboratory for Disease Gene Study, Hospital of University of Electronic Science and Technology and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, P. R. China
4The Center of Drug Discovery, Northeastern University, Boston, MA 02115, USA
5Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg 41345, Sweden
Tongbo Zhu, email: firstname.lastname@example.org
Keywords: Kras; PKCι; YAP1; survival; PDAC
Received: December 26, 2017 Accepted: March 06, 2018 Published: August 28, 2018
Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignant disease with 5-year survival rate of less than 6%. Activating mutations of Kras (mu-Kras) are often detected in most of PDAC patients. Although it has been known that oncogenic Kras is the driver of pancreatic cancer initiation and development, the underlying mechanisms by which mu-Kras promotes PDAC remain poorly understood. Here, we identify that PKCι is one of the crucial factors for supporting the survival of pancreatic cancer cells expressing mu-Kras. Our study demonstrates that after the knockdown of PKCι, the expression of the transcriptional co-activator YAP1 is decreased, which hinders the expression of the downstream target gene Mcl-1, and subsequently sensitizes pancreatic cancer MiaPaCa and PANC-1 cells experssing mu-Kras to apoptosis. In comparison, the suppression of PKCι has little impact on the viability of non-neoplastic pancreatic HPDE6-C7 cells. Moreover, the transient overexpression of oncogenic Kras in HPDE6-C7 elevates the expression of PKCι and YAP1 concomitantly. The upregulated YAP1 in HPDE6-C7/ mu-Kras cells is abolished once PKCι is suppressed, suggesting the linear relationship among mu-Kras, PKCι and YAP1. This phenomenon is further proven by the co-upregulation of PKCι and YAP1 in HPDE6-C7 cells stably transfected with mu-Kras. Taken together, our findings suggest that PKCι acts through promoting YAP1 function to promote the survival of pancreatic cancer cells expressing mu-Kras. It appears that targeting PKCι-YAP1 signaling is a feasible strategy for developing new therapeutics for treating pancreatic cancer patients.
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