Cellular prion protein in glioblastoma stem cells biology: its role in the acquisition of temozolomide resistance

• Grant number: 20/03714-8
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): February 01, 2022
• Effective date (End): January 31, 2023
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Marilene Hohmuth Lopes
• Grantee: Rebeca Piatniczka Iglesia
• Supervisor: Shiyuuan Cheng
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Northwestern University, Chicago, United States
• Associated to the scholarship: 19/12710-9 - Role of cellular prion protein in temozolomide resistance: emphasis on processes modulated by hypoxia, BP.PD

Abstract

The cellular prion protein, a glycoprotein abundantly expressed in central nervous system (CNS), present neurotrophic potential through the formation of multiprotein complexes with several ligands on the cell surface. Glioblastoma, a type of CNS tumor, extremely aggressive and 100% lethal, contains a subpopulation of cells responsible for therapy resistance, the glioblastoma stem cells (GSCs). Our group demonstrated that PrPC interaction with its main ligand, heat shock organizing protein (HOP), modulates human glioblastoma growth and the inhibition of this interaction with a HOP peptide (HOP230-245), that mimics PrPC binding site, is able to abrogate the effect in vivo. In GSCs, the inhibition of PrPC expression decreases stemness markers expression and self-renewal capability. HOP peptide inhibits self-renewal and proliferation mediated by PrPC, demonstrating its therapeutic potential targeting GSCs. Additionally, a PrPC peptide (PrPC106-126), which represent HOP binding site at 230-245 residues (HOP230-245) is able to promote the expression of hypoxia inducible factor 1± (HIF1±), a key factor associated with stemness and MGMT expression in GSCs. Remarkably, MGMT expression is related to resistance to temozolomide (TMZ), the most effective chemotherapeutic agent against GBM. Considering these findings, the main goal of this study is to evaluate the participation of PrPC in TMZ resistance in GSCs and the potential of HOP peptide in sensitize these cells through the modulation of MGMT via HIF1±. Thus, PrPC specific target to 106-126 domain could represent a novel and relevant target for management of glioblastoma biology with potential efficacy for conventional treatment with TMZ. (AU)