Role of PKC iota in Pancreatic Carcinogenesis

[unreadable] DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly lethal disease marked by a high level of chromosomal instability, including frequent chromosomal gains at 3q. PDAC is highly resistant to conventional chemotherapies; therefore, there is a dire need to identify new molecular targets for pancreatic cancer chemotherapy. Oncogenic K-ras and its downstream effector pathways are required for initiation and maintenance of transformation of pancreatic ductal epithelium. We have identified a requisite role for PKC( in oncogenic K-ras signaling in vitro and in vivo. PKC( plays a critical role in the transformed growth, invasion and migration of lung and colon cancer cells. PKC( is characterized as an oncogene in NSCLC based on the following observations: 1) PKC( is over-expressed in a majority of primary NSCLC tumors, 2) PKC( expression levels predict poor survival in NSCLC patients, 3) PKC( (located at 3q26) is frequently amplified in NSCLC and amplification drives PKC( expression and 4) disruption of PKC( function blocks transformed growth in NSCLC cell lines. Based on the similarities in oncogenic signal transduction pathways in lung, colon and pancreatic cancers, we hypothesize that PKC( also plays a requisite role in pancreatic cancer cell transformation. Specifically, we hypothesize that PKC( is required for PDAC cellular transformation and that either genetic or pharmacological inhibition of PKC( will block the transformed phenotype of pancreatic cancer cell lines by inhibiting PKC(-mediated oncogenic signaling. In addition, we hypothesize that the gain of chromosome 3q frequently observed in pancreatic cancer cell lines and tumors results in an increase in gene copy number and over-expression of PKC( in pancreatic tumors. Finally, we hypothesize that the level of expression of PKC( in pancreatic tumors will correlate with poor survival in pancreatic cancer patients. Three interrelated specific aims will test these hypotheses. In Specific Aim 1, we will test the hypothesis that PKC( is required for the transformed phenotype of pancreatic cancer cells by genetically and pharmacologically inhibiting PKC( function. In Specific Aim 2, we will test the hypothesis that PKC( plays a requisite role in the pro-carcinogenic signaling pathways that mediate the transformed phenotype of PDAC cells. In Specific Aim 3, we will evaluate the possibility that, similar to its role in non-small cell lung cancer, PKC( is an oncogene in pancreatic cancer. The successful completion of these aims will significantly enhance our knowledge of the role of PKC( in pancreatic cancer cell transformation, and will likely demonstrate that PKC( is a potential molecular target for the treatment of pancreatic cancer. [unreadable] [unreadable] [unreadable]