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Universidade De São Paulo Faculdade De Ciências Farmacêuticas UNIVERSIDADE DE SÃO PAULO FACULDADE DE CIÊNCIAS FARMACÊUTICAS BIOLOGIA MOLECULAR DE LEVEDURAS E SUA APLICAÇÃO BIOTECNOLÓGICA PARA ESTUDO DE MECANISMOS CELULARES DO CÂNCER E SEU TRATAMENTO. Gisele Monteiro SÃO PAULO 2017 2 UNIVERSIDADE DE SÃO PAULO FACULDADE DE CIÊNCIAS FARMACÊUTICAS BIOLOGIA MOLECULAR DE LEVEDURAS E SUA APLICAÇÃO BIOTECNOLÓGICA PARA ESTUDO DE MECANISMOS CELULARES DO CÂNCER E SEU TRATAMENTO. Gisele Monteiro Texto sistematizado apresentado à Faculdade de Ciências Farmacêuticas da Universidade de São Paulo para obtenção do Título de Professor Livre- Docente junto ao Departamento de Tecnologia Bioquímico-Farmacêutica. SÃO PAULO 2017 3 4 Nothing in life is to be feared, it is only to be understood. Marie Curie 5 DEDICATÓRIA Ao meu filho Gustavo, minha obra mais importante, por me ensinar a redimensionar os problemas e dar valor ao que de fato importa. À Universidade Estadual de Campinas (UNICAMP) por fazer de mim a profissional que sou, mas principalmente por me transformar num ser humano melhor. A todos os alunos e professores que contribuíram com seu trabalho, dedicação, apoio e amizade, possibilitando que eu tivesse material para produzir esse texto e para que eu pudesse construir uma história acadêmica. 6 AGRADECIMENTOS Aos meus pais, minha irmã, meus sobrinhos. O apoio de vocês me fortalece. Aos Professores Dr Adalberto Pessoa Junior e Dra Susana M.I. Saad pela amizade e apoio dentro do Departamento e da Faculdade. Vocês me acolheram e tornaram minha jornada mais leve. Aos meus alunos André de Abreu Cavalheiro, Tallybia Hayrian Trevisan, Gabriel Moretti de Almeida, Iris Munhoz Costa, Lucas de Sousa Cavalcante, Graziele Fonseca de Sousa, Paula Aryane Huang, Claudia Aznar Alesso, Gisele Cristina Ravaneli, Mariana Silva Moreira Leite, Lucas Fonseca Gonzaga, Henrique Pellin Biasoto, Beatriz de Araújo Bianchi Pedra, SeungHag Lee, Bruna de Souza Divino, Rafaela Coelho Correia, Mariane Augusta Domingues Rodrigues, Melina Cardoso dos Santos, Samarina Rodrigues Wlodarczyk, Marcela Valente Pimenta, Débora Fernandes Custodio, Karen Fulan Discola, Guilherme Meira Lima, Brian Effer Roldán. Vocês fizeram parte e contribuíram de forma essencial para essa etapa da minha vida. Aos funcionários do FBT e da FCF pelo apoio, compreensão e amizade. Aos meus amigos e colaboradores Prof Dr Marcos Antonio de Oliveira (UNESP-CLP), Prof Dr Anderson Ferreira da Cunha (UFSCar) e Profa Dra Camila Oresco dos Santos (Cold Spring Harbor Laboratory). Em especial, à Karen Fulan Discola pelo apoio sempre, pela amizade e pela inestimável ajuda com o memorial. Você me acalma. À minha irmã e amiga de ciência e da vida Simone Vidigal Alves. Admiro sempre. Aos meus amigos da FCF/USP Prof Dr Hélio A. Stefani, Profa Dra Sandra H. P. Farsky, Profa Dra Irene da Silva Soares. Aos amigos Alex Alfredo de Oliveira, Larissa Cristina Bentim, Rafaela Correia Coelho, Bruna de Souza Divino, Valker Feitosa, Talita Camila Nascimento e Tales Alexandre Costa e Silva, queridos pra sempre (PC). À Profa Dra Carlota de Oliveira Rangel Yagui pela parceria na Pós-Graduação, apoio e orientação para a Livre-Docência. Aos meus mentores de Ciência Prof Dr Luis E.S. Netto (IB/USP) e Prof Dr Gonçalo A. G. Pereira. Vocês me ensinaram a amar e respeitar a Ciência. À FAPESP pelo apoio financeiro essencial desde o começo da minha carreira. À CNPq e CAPES pelo apoio aos Programas e alunos de Pós-Graduação que fazem grande parte da Ciência desse país. À Universidade de São Paulo que me fascina, move e inspira com essa grandiosidade e força. 7 RESUMO MONTEIRO, G. Biologia molecular de leveduras e sua aplicação biotecnológica para estudo de mecanismos celulares do câncer e seu tratamento. 2017. 90 fls + anexos. Tese (Livre Docência) – Faculdade de Ciências Farmacêuticas da Universidade de São Paulo, São Paulo, 2017. Palavras-chave: Saccharomyces cerevisiae, Pichia pastoris, expressão heteróloga de proteínas, resistência aos antitumorais, estresse oxidativo, biofármaco. A levedura Saccharomyces cerevisiae é o eucarioto mais bem caracterizado quanto às vias metabólicas, celulares e funções de genes. Calcula-se que dos 6.000 genes codificadores de proteínas, pelo menos 3.000 tenham homologia com genes humanos. Além disso, mesmo quando não há homologia direta, os mecanismos moleculares são conservados e em ensaios de complementação de função é possível caracterizar funções análogas em humanos. Leveduras apresentam além de mecanismos conservados, diversas semelhanças metabólicas com células tumorais; talvez a mais marcante delas seja a repressão catabólica por glicose. Esse fenômeno causa uma superativação da via glicolítica e inibição da cadeia respiratória, o que lembra muito o efeito Warburg apresentado pelas células tumorais. Esse comportamento metabólico tem relação estreita com a homeostase redox celular. Estes fatores mostram o quanto à caracterização dessas células fúngicas pode ser aplicada ao entendimento e tratamento do câncer. Mesmo assim, 20 anos após o término do sequenciamento do genoma de S. cerevisiae, mais de 1.000 genes continuam anotados como não caracterizados. Além disso, as leveduras têm papel fundamental na produção biotecnológica de insumos farmacêuticos. Nesse texto sistematizado relato as contribuições dos meus estudos, juntamente com os resultados do meu grupo de pesquisa, usando a biologia molecular das leveduras, para responder questões aplicadas à compreensão de funções celulares (com destaque à resposta antioxidante), mecanismos moleculares de resposta aos antitumorais e produção de biofármacos. Além de modelo celular, as leveduras representam excelentes plataformas para expressão heteróloga de proteínas de interesse Biotecnológico-Farmacêutico. 8 ABSTRACT MONTEIRO, G. Molecular biology of yeast and its biotechnological application to study the cellular mechanisms of cancer and its treatment. 2017. NNN fls. Tese (Livre Docência) – Faculdade de Ciências Farmacêuticas da Universidade de São Paulo, São Paulo, 2017. Keywords: Saccharomyces cerevisiae, Pichia pastoris, heterologous protein expression, antitumor resistance, oxidative stress, biopharmaceutical. The yeast Saccharomyces cerevisiae is the most well characterized eukaryote for metabolic, cellular and gene functions. It is estimated that of the 6,000 protein-encoding genes, at least 3,000 have homology to human genes. Moreover, even when there is no direct homology, the molecular mechanisms are conserved and through function complementation assays it is possible to characterize analogous functions in humans. Yeasts present, in addition to conserved mechanisms, diverse metabolic similarities with tumor cells; perhaps the most remarkable of them is the catabolic repression by glucose. This phenomenon causes an over activation of the glycolytic pathway and inhibition of the respiratory chain, which strongly resembles the Warburg effect presented by tumor cells. This metabolic behavior is closely related to cellular redox homeostasis. These factors show how much the characterization of these fungal cells can be applied to the understanding and treatment of cancer. Even so, 20 years after the end of the sequencing of the S. cerevisiae genome, more than 1,000 genes remain annotated as uncharacterized. In addition, yeasts play a key role in the biotechnological production of pharmaceutical inputs. In this systematized text I show the contributions of my studies, together with the results of my research group, using molecular biology of yeast to answer questions applied to understanding cellular functions (with emphasis on the antioxidant response), molecular response mechanisms to antitumor drugs and biopharmaceutical production. In addition to cellular model, yeasts represent excellent platforms for the heterologous expression of proteins of Biotechnological- Pharmaceutical interest. 9 TRABALHOS ANEXADOS (por ordem de exemplificação no texto). Monteiro G, Horta BB, Pimenta DC, Augusto O, Netto LES. Reduction of 1-Cys peroxiredoxins by ascorbate changes the thiol-specific antioxidant paradigm, revealing another function of vitamin C. Proc Natl Acad Sci U S A 2007;104:4886-91. doi:10.1073/pnas.0700481104. (ANEXO 1). Costa IM, Nasser TH, Demasi M, Nascimento RM, Netto LE, Miyamoto S, Prado FM, Monteiro G. The promoter of filamentation (POF1) protein from Saccharomyces cerevisiae is an ATPase involved in the protein quality control process. BMC Microbiol 2011;11(268):1-11. doi:10.1186/1471-2180-11-268. (ANEXO 2). Moretti-Almeida G, Netto LES, Monteiro G. The essential gene YMR134W from Saccharomyces cerevisiae is important for appropriate mitochondrial iron utilization and the ergosterol biosynthetic pathway. FEBS Lett 2013;587:3008-13. doi:10.1016/j.febslet.2013.07.024. (ANEXO 3). Alesso CA, Discola KF, Monteiro G. The gene ICS3 from the yeast Saccharomyces cerevisiae is involved in copper homeostasis dependent on extracellular pH. Fungal Genet Biol 2015;82:43-50. doi:10.1016/j.fgb.2015.06.007. (ANEXO 4). Sousa GF, Lima MA, Custodio DF, Freitas VM, Monteiro G. Chemogenomic study of Carboplatin in Saccharomyces cerevisiae: inhibition of the NEDDylation process overcomes cellular resistance mediated by HuR and Cullin proteins. Plos One 2015;10(e0145377):1-18. doi:10.1371/journal.pone.0145377. (ANEXO 5). Santos JH, Costa IM, Molino JV, Leite MS, Pimenta MV, Coutinho JA, Pessoa Jr A, Ventura SP, Lopes AM, Monteiro G. Heterologous expression and purification of active L-asparaginase I of Saccharomyces cerevisiae in Escherichia coli host. Biotechnol Prog 2016 [In press]. doi:10.1002/btpr.2410. (ANEXO 6). Costa
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