Role of protein disulfide isomerase in the regulation of Nox1 activation and EGFR signaling in cancer

• Grant number: 16/07004-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: July 28, 2016
• End date: July 27, 2017
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Lucia Rossetti Lopes
• Grantee: Simone Marcieli Sartoretto
• Supervisor: Francis Joseph Miller
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Duke University, United States
• Associated to the scholarship: 14/09334-1 - Role of protein disulfide isomerase (PDI) in the EGFR activation and regulation of the expression/activity of the NADPH oxidase in vascular smooth muscle cells, BP.PD

Abstract

Under physiological conditions, formation of reactive oxygen species (ROS) is counterbalanced by endogenous antioxidant defenses systems. When ROS production exceeds cellular antioxidant capacity, oxidative stress can cause damage to the cell. In normal physiologic conditions, Nox-derived ROS act as second messengers in cell signaling and modulate processes such as gene expression, cell proliferation, migration, and angiogenesis. However, in pathological conditions such as cancer, Nox expression and activity are increased, leading to elevated ROS levels and cytotoxic damage to intracellular molecules including lipid, DNA, and proteins. The concept that Nox-1 derived ROS affect cancer cells is described in the literature, but the specific mechanisms and effects are not well understood. Our group has been extensively studying protein disulfide isomerase (PDI) as a regulator of NADPH oxidase activity. We recently showed that PDI expression is increased in vessel of hypertension rats, and other groups have demonstrated a role for PDI in diabetes, neurodegenerative conditions and cancer. But the role of PDI in cancer progression is not well established. In preliminary data, we found that an increase in PDI levels caused an increase in Nox1 expression via a mechanism that involves epidermal growth factor receptor (EGFR) activation. Multiple studies have shown increased levels of the EGFR in tumors and diverse EGFR inhibitors have been used to treat cancer. But nothing is known about the relationship between PDI/NOX1 and EGFR in cancer.