Role of dual specificity phosphatases (DUSP) in the induction of oxidative stress in pancreatic adenocarcinoma cells

• Grant number: 18/11705-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): August 01, 2018
• Effective date (End): July 31, 2019
• Field of knowledge: Biological Sciences - Genetics
• Principal Investigator: Vanessa da Silva Silveira
• Grantee: Bruno Mari Fredi
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 15/10694-5 - Dual specificity phosphatases activity on map kinases signaling regulation: impact on pancreatic ductal adenocarcinoma metabolic reprogramming, AP.JP

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is a malignant tumor which affects the pancreatic ductal cells and corresponds to 4% of all malignant tumors. It is highly aggressive, with a very unfavorable diagnosis and represents the 7th cause of cancer death by year in the world. 95% of the tumors that affects the pancreas occurs in the ductal cells. Little is known yet about the molecular mechanisms involved with PDAC. However, it is known that the mutation KRASG12D is present in the majority of PDAC cases. This mutation results in a protein in his constitutively active state being unable of hydrolyse GTP and providing in that way the downstream permanent active pathways. Among the activated pathways are the mitogen-activated protein kinase (MAPKs). The MAPKs control countless essencial process pathways for the cell survival and for the tumoral development as cellular proliferation, apoptosis, chemo resistance and metabolism alterations. Among these metabolic alterations that could be mediated by the MAPKs pathways is the metabolic reprogramming and an elevated production of NADPH and "ROS detoxification" by the activation of a non-canonical pathway which results in low levels of ROS, fundamental for the tumoral development of PDAC. Due to this extreme importance of the MAPKs in several cellular processes this kinases must be very well regulated and, between the regulation processes, are the negative feedback mechanisms exercised by the dual-specificity phosphatase proteins (DUSPs) which specifically dephosphorylate the MAPKs. The role of DUSPs has already been elucidated in other tumors. However, little is known about the acting of these phosphatases in the controlling of the oxidative stress in PDAC. On this, the present project aims to investigate the connection between DUSPs and the oxidative stress control in PDAC.