PKCι and YAP1 are crucial in promoting pancreatic tumorigenesis.

Peipei Wang,Suthakar Ganapathy,Pauline Isakson,Changyan Chen,Jiao Chen,Hongmei Zhang,Dapeng Wei,Tongbo Zhu,Dingding Zhang

doi:10.18632/oncotarget.25127

Abstract

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.

Highlights

IntroductionPancreatic ductal adenocarcinoma (PDAC) remains to be one of the most incurable lethal cancers with less than 6% patients surviving more than 5 years [1], a survival rate that hardly improves over the past few decades
Despite extensive research efforts, pancreatic ductal adenocarcinoma (PDAC) remains to be one of the most incurable lethal cancers with less than 6% patients surviving more than 5 years [1], a survival rate that hardly improves over the past few decades
Mutant Kras, a member of the Ras gene family and the most prevalent genetic alteration in cancer, has been identified in >90% Pancreatic ductal adenocarcinoma (PDAC) and documented to be indispensable in driving the initiation and development www.oncotarget.com of PDAC [2, 3], and recent advances in the development of mutations of Kras (mu-Kras) specific inhibitor have offered some hope in targeting Kras protein for treatment [48], to date no pharmacological approaches that suppress the activity of this mutant protein have reached the clinic, compelling further delving into the signaling pathways engaged by Kras to identify alternative targets that are essential for PDAC maintenance and amenable to therapeutic intervention

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the most incurable lethal cancers with less than 6% patients surviving more than 5 years [1], a survival rate that hardly improves over the past few decades. Protein kinase C (PKC) is a family of serine/ threonine kinases that are classified into conventional, novel and atypical PKC subgroups according to their structures and the co-factors they need for activation. A variety of the PKC family members, for instance the conventional PKC isozymes α and β, and the novel PKC isozyme δ, have been illustrated to function coordinately to support the survival of cells carrying hyperactive Ras [4]. The two atypical PKC isozymes, ι and ζ, have been defined as pro-proliferative in a diversity of cancers, with PKCι being recognized as an oncogene that plays pivotal roles in the transformation of numerous tumors including PDAC [5,6,7]. The interaction between PKCι and Kras, as well as its contribution to the PDAC tumorigenesis and maintenance is not fully elucidated

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