Mechanisms associated with the function of prion protein and its ligand STI1/Hop: therapeutic approaches

• Grant number: 09/14027-2
• Support Opportunities: Research Projects - Thematic Grants
• Duration: December 01, 2010 - April 30, 2017
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Vilma Regina Martins
• Grantee: Vilma Regina Martins
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated researchers: Cícero Galli Coimbra ; Fernando Augusto Soares ; Glaucia Noeli Maroso Hajj ; Helena Regina Comodo Segreto ; Isabela Werneck da Cunha ; Marco Antonio Maximo Prado ; Maria Aparecida Juliano ; Maria José da Silva Fernandes ; Marilene Hohmuth Lopes ; Rafael Linden ; Renata de Almeida Coudry ; Rita de Cassia Sinigaglia ; Roberto Araujo Segreto ; Suely Kazue Nagahashi Marie ; Vania Ferreira Prado
• Associated grant(s): 15/50428-2 - The patient-derived xenograft as a platform to identify cancer biomarkers in circulating exosomes in renal cell carcinoma, AP.R SPRINT; 14/50266-0 - The role of prions in the control of insulin response, AP.R
• Associated scholarship(s): 13/26097-0 - Analysis of PrPC/STI1 signaling and possible therapeutic role in Amyotrophic Lateral Sclerosis, BP.PD; 13/04913-0 - Identification and characterization of the extracellular vesicles secreted by rectal cancer and their relation with the response to neoadjuvant treatment, BP.DR; 12/23285-8 - Characterization of extracellular vesicles secreted by cancer cells and evaluation of their role in the progression, metastasis and prognosis of head and neck squamous cell carcinoma, BP.PD; + associated scholarships 12/19019-0 - Regulation of STAT3 activity and the role of secreted STI1/Hop protein in glioblastoma multiforme, BP.DD; 11/20853-2 - INTERACTIONS OF THE PRION PROTEIN AND ITS LIGANDS STI1 AND LAMININ: POSSIBLE IMPLICATIONS FOR ALZHEIMER'S DISEASE, BP.DR; 11/21350-4 - Protein Synthesis Regulation by Sumoylation, BP.PD; 11/18718-0 - The role of PrPc-HOP complex in colon tumors, BP.DD; 10/20796-6 - Prion protein and its STI1 ligands and laminin: possible implications in Alzheimer's Disease, BP.PD; 10/13654-0 - Regulation of activity of STAT3 for STI1/Hop in glioblastoma., BP.MS; 10/19200-1 - Identification of mechanisms of protein STI1/Hop secretion, BP.PD - associated scholarships

Abstract

The prion protein (PrPC) plays major roles in cellular functions by binding to diverse proteins, forming multi-protein complexes and organizing signaling platforms. These protein complexes need to be better evaluated at molecular and cellular level in order to understand how PrPC associations trigger different cellular signals. PrPC association with Stress-inducible protein 1 or its human homolog Hop (STI1/Hop), which is secreted by astrocytes, promotes neuronal and glial survival and differentiation in vitro, modulates the proliferation of neural stem cells and tumor cells in culture and supports immunological processes. STI1/Hop performs neurotrophic activities and the molecular mechanisms, in particular post-translation modifications, associated with the secretion and regulation of this protein are unknown and need to be approached. It is also a major challenge to identify the functions of STI1/Hop in vivo by using conditional and constitutive STI1/Hop knockout mice, which have been recently generated by our group. Due to its positive role in cell survival (particulary in neurons) and proliferation the complex PrPC-STI1/Hop is a relevant therapeutic target. Its in vivo role in the biology or adult stem cells, in neuroprotection in injury models such as ischemia and radiotherapy, in the proliferation of tumor cells as well as in immunological mechanisms will be largely explored. (AU)

Scientific publications

(22)

(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)

HARTMANN, CAMILA ARANTES; MARTINS, VILMA REGINA; SOUZA LIMA, FLAVIA REGINA. High levels of Cellular Prion Protein improve astrocyte development. FEBS Letters, v. 587, n. 2, p. 238-244, JAN 16 2013. (09/14027-2)

OSTAPCHENKO, VALERIY G.; BERALDO, FLAVIO H.; MOHAMMAD, AMRO H.; XIE, YU-FENG; HIRATA, PEDRO H. F.; MAGALHAES, ANA C.; LAMOUR, GUILLAUME; LI, HONGBIN; MACIEJEWSKI, ANDRZEJ; BELROSE, JILLIAN C.; et al. The Prion Protein Ligand, Stress-Inducible Phosphoprotein 1, Regulates Amyloid-beta Oligomer Toxicity. JOURNAL OF NEUROSCIENCE, v. 33, n. 42, p. 16552-16564, OCT 16 2013. (09/14027-2, 12/04370-4)

CAETANO, FABIANA A.; BERALDO, FLAVIO H.; HAJJ, GLAUCIA N. M.; GUIMARAES, ANDRE L.; JUERGENSEN, SOFIA; WASILEWSKA-SAMPAIO, ANA PAULA; HIRATA, PEDRO H. F.; SOUZA, IVANA; MACHADO, CLEITON F.; WONG, DAISY Y. -L.; et al. Amyloid-beta oligomers increase the localization of prion protein at the cell surface. Journal of Neurochemistry, v. 117, n. 3, p. 538-553, MAY 2011. (08/00390-5, 09/14027-2)

SANTOS, TIAGO G.; SILVA, IARA R.; COSTA-SILVA, BRUNO; LEPIQUE, ANA PAULA; MARTINS, VILMA R.; LOPES, MARILENE H.. Enhanced Neural Progenitor/Stem Cells Self-Renewal via the Interaction of Stress-Inducible Protein 1 with the Prion Protein. Stem Cells, v. 29, n. 7, p. 1126-1136, JUL 2011. (03/13189-2, 07/08410-2, 09/14027-2)

ALVARENGA, ARTHUR WILLIAM; MACHADO, LUIS EDUARDO; RODRIGUES, BRUNA ROZ; SULLA LUPINACCI, FERNANDA CRISTINA; SANEMASTU, PAULO; MATTA, EDUARDO; ROFFE, MARTIN; BLEGGI TORRES, LUIS FERNANDO; DA CUNHA, ISABELA WERNECK; MARTINS, VILMA REGINA; et al. Evaluation of Akt and RICTOR Expression Levels in Astrocytomas of All Grades. JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, v. 65, n. 2, p. 93-103, FEB 2017. (14/15550-9, 09/14027-2)

WASILEWSKA-SAMPAIO, ANA PAULA; SANTOS, TIAGO G.; LOPES, MARILENE HOHMUTH; CAMMAROTA, MARTIN; MARTINS, VILMA REGINA. The growth of glioblastoma orthotopic xenografts in nude mice is directly correlated with impaired object recognition memory. Physiology & Behavior, v. 123, p. 55-61, JAN 17 2014. (09/14027-2)

ALVARENGA, ARTHUR W.; COUTINHO-CAMILLO, CLAUDIA M.; RODRIGUES, BRUNA R.; ROCHA, RAFAEL M.; TORRES, LUIZ FERNANDO B.; MARTINS, VILMA R.; DA CUNHA, ISABELA W.; HAJJ, GLAUCIA N. M.. A Comparison between Manual and Automated Evaluations of Tissue Microarray Patterns of Protein Expression. JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, v. 61, n. 4, p. 272-282, APR 2013. (09/14027-2, 12/04370-4)

IGLESIA, REBECA PIATNICZKA; PRADO, MARIANA BRANDAO; CRUZ, LILIAN; MARTINS, VILMA REGINA; SANTOS, TIAGO GOSS; LOPES, MARILENE HOHMUTH. Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells. STEM CELL RESEARCH & THERAPY, v. 8, APR 17 2017. (13/19860-0, 15/04122-9, 11/13906-2, 09/14027-2)

DA LUZ, MARCIO H. M.; PERES, ITALO T.; SANTOS, TIAGO G.; MARTINS, VILMA R.; ICIMOTO, MARCELO Y.; LEE, KIL S.. Dopamine induces the accumulation of insoluble prion protein and affects autophagic flux. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 9, FEB 2 2015. (13/22413-5, 12/18093-2, 08/06152-9, 09/14027-2)

BAPTISTELLA, ANTUANI R.; SALLES DIAS, MARCOS VINICIOS; AGUIAR, JR., SAMUEL; BEGNAMI, MARIA D.; MARTINS, VILMA R.. Heterogeneous expression of A33 in colorectal cancer: possible explanation for A33 antibody treatment failure. ANTI-CANCER DRUGS, v. 27, n. 8, p. 734-737, SEP 2016. (13/04913-0, 09/14027-2)

MUNOZ, JUAN J.; DRIGO, SANDRA A.; KUASNE, HELLEN; VILLACIS, ROLANDO A. R.; MARCHI, FABIO A.; DOMINGUES, MARIA A. C.; LOPES, ADEMAR; SANTOS, TIAGO G.; ROGATTO, SILVIA R.. A comprehensive characterization of cell cultures and xenografts derived from a human verrucous penile carcinoma. TUMOR BIOLOGY, v. 37, n. 8, p. 11375-11384, AUG 2016. (09/52088-3, 10/51601-6, 09/14027-2)

RODRIGUES, BRUNA R.; QUEIROZ-HAZARBASSANOV, NICOLLE; LOPES, MARILENE H.; BLEGGI-TORRES, LUIS F.; SUZUKI, SERGIO; CUNHA, ISABELA W.; SANEMATSU, PAULO; MARTINS, VILMA R.. Nuclear unphosphorylated STAT3 correlates with a worse prognosis in human glioblastoma. PATHOLOGY RESEARCH AND PRACTICE, v. 212, n. 6, p. 517-523, 2016. (10/13654-0, 09/14027-2)

SANTOS, TIAGO G.; LOPES, MARILENE H.; MARTINS, VILMA R.. Targeting prion protein interactions in cancer. PRION, v. 9, n. 3, p. 165-173, MAY 4 2015. (11/13906-2, 09/14027-2)

BAPTISTEILA, ANTUANI RAFAEL; LANDEMBERGER, MICHELE CHRISTINE; SALLES DIA, MARCOS VINICIOS; GIUDIC, FERNANDA SALGUEIREDO; RODRIGUES, BRUNA ROZ; COMBAS EUFRAZIO DA SILV, PETRUS PAULO; CASSINELA, EDSON KUATELELA; LACERDA, TONIELLI CRISTINA; MARCHI, FABIO ALBUQUERQUE; PAES LEME, ADRIANA FRANCO; et al. Rab5C enhances resistance to ionizing radiation in rectal cancer. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 97, n. 6, p. 855-869, JUN 2019. (10/19200-1, 09/14027-2, 13/04913-0, 11/18718-0)

BERALDO, FLAVIO H.; THOMAS, ANU; KOLISNYK, BENJAMIN; HIRATA, PEDRO H.; DE JAEGER, XAVIER; MARTYN, AMANDA C.; FAN, JUE; GONCALVES, DANIELA F.; COWAN, MATTHEW F.; MASOOD, TALAL; et al. Hyperactivity and attention deficits in mice with decreased levels of stress-inducible phosphoprotein 1 (STIP1). Disease Models & Mechanisms, v. 8, n. 11, p. 1457-1466, NOV 2015. (09/14027-2)

LOPES, M. H.; SANTOS, T. G.; RODRIGUES, B. R.; QUEIROZ-HAZARBASSANOV, N.; CUNHA, I. W.; WASILEWSKA-SAMPAIO, A. P.; COSTA-SILVA, B.; MARCHI, F. A.; BLEGGI-TORRES, L. F.; SANEMATSU, P. I.; et al. Disruption of prion protein-HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival. Oncogene, v. 34, n. 25, p. 3305-3314, JUN 2015. (07/08410-2, 12/19019-0, 09/14027-2, 04/12133-6, 10/20796-6)

ROFFE, MARTIN; LUPINACCI, FERNANCLA C.; SOARES, LUANA C.; HAJJ, GLAUCIA N.; MARTINS, VILMA R.. Two widely used RSK inhibitors, BI-D1870 and SL0101, alter mTORC1 signaling in a RSK-independent manner. CELLULAR SIGNALLING, v. 27, n. 8, p. 1630-1642, AUG 2015. (13/25025-6, 11/21350-4, 13/03315-2, 09/14027-2, 12/04370-4)

DIAS, MARCOS V. S.; TEIXEIRA, BIANCA L.; RODRIGUES, BRUNA R.; SINIGAGLIA-COIMBRA, RITA; PORTO-CARREIRO, ISABEL; ROFFE, MARTIN; HAJJ, GLAUCIA N. M.; MARTINS, VILMA R.. PRNP/prion protein regulates the secretion of exosomes modulating CAV1/caveolin-1-suppressed autophagy. AUTOPHAGY, v. 12, n. 11, p. 2113-2128, 2016. (12/19019-0, 10/19200-1, 09/14027-2)

HAJJ, GLAUCIA N. M.; ARANTES, CAMILA P.; SALLES DIAS, MARCOS VINICIOS; ROFFE, MARTIN; COSTA-SILVA, BRUNO; LOPES, MARILENE H.; PORTO-CARREIRO, ISABEL; RABACHINI, TATIANA; LIMA, FLAVIA R.; BERALDO, FLAVIO H.; et al. The unconventional secretion of stress-inducible protein 1 by a heterogeneous population of extracellular vesicles. CELLULAR AND MOLECULAR LIFE SCIENCES, v. 70, n. 17, p. 3211-3227, SEP 2013. (09/14027-2, 12/04370-4)

BERTUCHI, FERNANDA R.; BOURGEON, DOMINIQUE M. G.; LANDEMBERGER, MICHELE C.; MARTINS, VILMA R.; CERCHIARO, GISELLE. PrPC displays an essential protective role from oxidative stress in an astrocyte cell line derived from PrPC knockout mice. Biochemical and Biophysical Research Communications, v. 418, n. 1, p. 27-32, FEB 3 2012. (09/14027-2)

SOUSA DE LACERDA, TONIELLI CRISTINA; COSTA-SILVA, BRUNO; GIUDICE, FERNANDA SALGUEIREDO; SALLES DIAS, MARCOS VINICIOS; DE OLIVEIRA, GABRIELA PINTAR; TEIXEIRA, BIANCA LUISE; DOS SANTOS, TIAGO GOSS; MARTINS, VILMA REGINA. Prion protein binding to HOP modulates the migration and invasion of colorectal cancer cells. CLINICAL & EXPERIMENTAL METASTASIS, v. 33, n. 5, p. 441-451, JUN 2016. (12/23285-8, 13/26097-0, 10/19200-1, 09/14027-2, 11/18718-0, 11/20853-2)

SANTOS, TIAGO GOSS; MARTINS, VILMA REGINA; MAROSO HAJJ, GLAUCIA NOELI. Unconventional Secretion of Heat Shock Proteins in Cancer. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 18, n. 5, MAY 2017. (14/15550-9, 15/02098-3, 09/14027-2)