Role of cellular prion protein in temozolomide resistance: emphasis on processes modulated by hypoxia

• Grant number: 19/12710-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): July 01, 2019
• Effective date (End): January 31, 2022
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Marilene Hohmuth Lopes
• Grantee: Rebeca Piatniczka Iglesia
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/15557-4 - Prion protein and its partners: emerging targets for glioblastoma stem cell based-therapy, AP.JP2
• Associated scholarship(s): 20/03714-8 - Cellular prion protein in glioblastoma stem cells biology: its role in the acquisition of temozolomide resistance, BE.EP.PD

Abstract

Glioblastoma multiforme (GBM), the most aggressive type of brain tumor, is initiated and maintained by a subpopulation of tumorigenic cells called glioblastoma stem cells (GSCs) that contribute to progression and resistance to therapy. In GBM therapy the alkylating agent temozolomide (TMZ) is the most effective chemotherapist, but resistance is frequent. One of the mechanisms of resistance to TMZ involves the modulation of MGMT expression by Hypoxia Induced Factor 1± (HIF1±) in GSCs, a molecule highly expressed in GSCs niches which promotes cell survival through the induction of anti-apoptotic proteins expression. Recent data from our group demonstrate that blocking the interaction between the cellular prion protein (PrPC ) and one of its main ligands, the heat shock organizing protein (HOP) with a HOP peptide (HOP230-245) is able to inhibit GSCs self-renewal and glioblastomas growth in vivo. PrPC silencing decreases the expression of stem cells markers, selfrenewal and tumorigenesis of GSCs. Remarkably, a PrPC peptide which mimics HOP binding site (PrPC 106-126) is able to promote HIF1± expression, inducing protection against cell death. Considering these data together, this study aims to identify the participation of PrPC in the TMZ resistance of GSCs mediated by HIF1±. In addition, we will evaluate HOP230-245 peptide potential in sensitizing GSCs to TMZ, since it binds to PrPC at the specific site 106-126 being able to compete with other PrPC ligands by this domain and, consequently, inhibit functions modulated by these interactions. Preliminary trials on stem cell enriched glioblastoma lineage cultures suggest that treatment with TMZ-associated HOP230-245 increases cell death compared to TMZ or the peptide alone, sensitizing cells to TMZ treatment and increasing their efficiency. Finally, the search for therapeutic-combined strategies targeting GSCs is imperative to improve the efficacy of treatments against this incurable tumor.

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PRADO, MARIANA BRANDAO; MELO ESCOBAR, MARIA ISABEL; ALVES, RODRIGO NUNES; COELHO, BARBARA PARANHOS; FERNANDES, CAMILA FELIX DE LIMA; BOCCACINO, JACQUELINE MARCIA; IGLESIA, REBECA PIATNICZKA; LOPES, MARILENE HOHMUTH. Prion Protein at the Leading Edge: Its Role in Cell Motility. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 18, p. 18-pg., 2020-09-01. (19/14952-0, 19/11097-1, 19/14741-9, 17/26158-0, 19/12710-9, 18/15557-4, 20/07450-5, 20/04687-4)

IGLESIA, REBECA PIATNICZKA; PRADO, MARIANA BRANDAO; ALVES, RODRIGO NUNES; ESCOBAR, MARIA ISABEL MELO; FERNANDES, CAMILA FELIX DE LIMA; FORTES, AILINE CIBELE DOS SANTOS; SOUZA, MARIA CLARA DA SILVA; BOCCACINO, JACQUELINE MARCIA; CANGIANO, GIOVANNI; SOARES, SAMUEL RIBEIRO; et al. Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 10, p. 17-pg., 2022-06-15. (21/05287-2, 21/13114-0, 18/15557-4, 19/14741-9, 19/11097-1, 20/03714-8, 20/04687-4, 19/12710-9, 17/26158-0, 20/07450-5, 19/06971-4, 20/05443-1, 21/13070-3)

ALVES, RODRIGO NUNES; IGLESIA, REBECA PIATNICZKA; PRADO, MARIANA BRANDAO; MELO ESCOBAR, MARIA ISABEL; BOCCACINO, JACQUELINE MARCIA; FERNANDES, CAMILA FELIX DE LIMA; COELHO, BARBARA PARANHOS; FORTES, AILINE CIBELE; LOPES, MARILENE HOHMUTH. A New Take on Prion Protein Dynamics in Cellular Trafficking. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 20, OCT 2020. (20/07450-5, 17/26158-0, 19/14952-0, 19/11097-1, 20/04687-4, 18/15557-4, 19/12710-9, 19/14741-9)

DE LIMA FERNANDES, CAMILA FELIX; IGLESIA, REBECA PIATNICZKA; MELO-ESCOBAR, MARIA ISABEL; PRADO, MARIANA BRANDAO; LOPES, MARILENE HOHMUTH. Chaperones and Beyond as Key Players in Pluripotency Maintenance. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 7, AUG 2 2019. (18/15557-4, 17/26158-0, 18/19320-9, 19/12710-9, 19/11097-1, 17/20271-0)

COELHO, BARBARA PARANHOS; DE LIMA FERNANDES, CAMILA FELIX; BOCCACINO, JACQUELINE MARCIA; DA SILVA SOUZA, MARIA CLARA; MELO-ESCOBAR, MARIA ISABEL; ALVES, RODRIGO NUNES; PRADO, MARIANA BRANDAO; IGLESIA, REBECA PIATNICZKA; CANGIANO, GIOVANNI; MAZZARO, GIULIA LA ROCCA; et al. Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma. FRONTIERS IN ONCOLOGY, v. 10, NOV 12 2020. (19/14552-1, 19/14952-0, 17/26158-0, 20/04687-4, 19/06971-4, 19/11097-1, 19/12710-9, 20/07450-5, 18/15557-4, 19/14741-9)

IGLESIA, REBECA PIATNICZKA; DE LIMA FERNANDES, CAMILA FELIX; COELHO, BARBARA PARANHOS; PRADO, MARIANA BRANDAO; MELO ESCOBAR, MARIA ISABEL; DONA RODRIGUES ALMEIDA, GUSTAVO HENRIQUE; LOPES, MARILENE HOHMUTH. Heat Shock Proteins in Glioblastoma Biology: Where Do We Stand?. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 20, n. 22, NOV 2019. (18/15557-4, 17/26158-0, 18/19320-9, 19/14952-0, 17/20271-0, 19/12710-9, 19/11097-1)