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Identification of PKC¹/» signaling binding partners in pancreatic cancer

Grant number: 17/14696-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): December 01, 2017
Effective date (End): November 30, 2019
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Deborah Schechtman
Grantee:Damian Emilio Berardi
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Ductal adenocarcinoma is the most common malignancy of the pancreas and is characterized by a remarkable resistance to most of the available treatments, including chemotherapy, radiotherapy and molecularly targeted therapy. One of the hallmarks in pancreatic cancer is invasion and metastasis upon early onset of disease spreading. Atypical protein kinase C (aPKC), serine/threonine kinases, have been described as key components in determining cell polarity by interacting with the Partitioning defective complex (Par complex). Specifically, with regards to Pancreatic cancer, previous studies have shown that PKC¹/» plays an important role in invasion and metastasis. Furthermore, PKC¹/» is significantly over-expressed in this type of cancer. In fact, Scotti and collaborators found that inhibition of PKC¹/» expression blocks Pancreatic Ductal Adenocarcinoma (PDAC) cell growth in vitro and tumorigenicity in vivo as well as pancreatic tumor angiogenesis and metastasis. However, the molecular mechanisms by which PKC¹/» leads to tumorigenesis are still not clear. PKC¹/» available inhibitors are not specific and lead to drug resistance possibly because frequent mutations are found in the catalytic domain of the kinase. Specifically inhibiting depict protein-protein interactions of PKC¹/» with target proteins could be more effective.Thus, in the present project we intend to identify and characterize PKC¹/» substrates and binding proteins and determine the signaling pathways that are involved in the loss of epithelial polarity, migration and invasion of pancreatic cancer cells.