Interação funcional e molecular da proteína anexina A1 e do quimioterápico cisplatina no carcinoma de colo de útero
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Data
2018-06-05
Autores
Prates, Janesly
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
O câncer de colo de útero apresenta altas taxas de incidência e mortalidade, e sua progressão depende de características genéticas e interações das células tumorais, epiteliais e inflamatórias. A maioria dos protocolos de tratamentos, neste tipo de câncer, utiliza a Cisplatina (Cis). No entanto, este quimioterápico induz efeitos colaterais, como a nefrotoxicidade, por isso alternativas terapêuticas tem sido estudadas, como a proteína anexina A1 (ANXA1), que apresenta ações anti-inflamatória, antiproliferativas e também modula a expressão do gene Inibidor de Diferenciação ao DNA 1 (ID1) no processo tumoral. Com essas considerações, o objetivo do trabalho foi investigar a interação molecular dos mediadores ANXA1 e ID1 com a Cis em linhagem celular, e relacionar com tecidos neoplásicos intraepiteliais no processo tumorigênico cervical. As células SiHa (carcinoma epidermóide de cérvice), tratadas com o peptídeo da anexina A1 (AC2-26), Cis e AC2-26+Cis, foram avaliadas nos ensaios de proliferação, citotoxicidade, migração celular, apoptose, imunolocalização e expressões dos genes ANXA1 e ID1, e das proteínas ANXA1, ID1 e ERK1/2 (Quinase Regulada Extracelularmente 1/2). As amostras de tecidos cervicais foram analisadas histopatologicamente e as expressões proteicas de ANXA1 e ID1, por imuno-histoquímica. Os tratamentos, em todos os grupos, diminuíram a proliferação e migração celular, sem efeitos citotóxicos. Enquanto, Cis e AC2-26+Cis induziram as células aos processos de apoptose tardia, diminuição da expressão do ID1 e aumento da ANXA1, indicando a atividade antineoplásica da cisplatina. A administração Cis e AC2-26+Cis inativou ERK1/2 fosforilada e induziu a translocação nuclear da ANXA1. As expressões das proteínas ID1 e ANXA1 foram observadas nas amostras teciduais de Neoplasias Intraepiteliais Cervicais (NIC), com intensa imunomarcação de ID1 em NIC III. Em conjunto, os dados obtidos nesse trabalho fornecem entendimento adicional do mecanismo de ação da cisplatina na modulação dos mediadores ID1 e ANXA1 no processo tumorigênico. Esses achados podem delinear novas estratégias para a intervenção terapêutica no câncer de colo de útero.
Cervical cancer presents high rates of incidence and mortality, and its progression depends on genetic characteristics and tumor interactions, epithelial and inflammatory cells. Most treatment protocols, in this type of cancer, use Cisplatin (Cis). However, this chemotherapeutic induces side effects such as nephrotoxicity, so alternative therapies have been studied, such as the Annexin A1 protein (ANXA1), which exhibits anti-inflammatory, antiproliferative actions and also modulates expression of the Inhibitor of Differentiation to DNA 1 (ID1) gene in the tumor process. With these considerations, the objective of this work was to investigate the molecular interaction of the ANXA1 and ID1 mediators with Cis in cell line, and to relate with intraepithelial neoplastic tissues in the cervical tumorigenic process. SiHa (cervical epidermoid carcinoma) cells treated with the annexin A1 (AC2-26) peptide, Cis and AC2-26+ Cis, were evaluated in the proliferation, cytotoxicity, cell migration, apoptosis, immunolocalization and gene expression assays ANXA1 and ID1, and of the ANXA1, ID1 and ERK1/2 (Extracellular signalregulated kinase) proteins. Cervical tissue samples were analyzed histopathologically and the protein expression of ANXA1 and ID1 by immunohistochemistry. Treatments, in all groups, decreased cell proliferation and migration, without cytotoxic effects. While, Cis and AC2-26+ Cis induced the cells to processes of late apoptosis, decreased expression of ID1 and increased ANXA1, indicating the antineoplastic activity of cisplatin. Cis and AC2-26+ Cis administration inactivated ERK1/2 phosphorylated and induced nuclear translocation of ANXA1. Expressions of the ID1 and ANXA1 proteins were observed in tissue samples from Cervical Intraepithelial Neoplasia (CIN), with intense ID1 immunolabeling in CIN III. Together, the data obtained in this work provide additional understanding of the mechanism of action of cisplatin in the modulation of mediators ID1 and ANXA1 in the tumorigenic process. These findings may outline new strategies for therapeutic intervention in cervical cancer.
Cervical cancer presents high rates of incidence and mortality, and its progression depends on genetic characteristics and tumor interactions, epithelial and inflammatory cells. Most treatment protocols, in this type of cancer, use Cisplatin (Cis). However, this chemotherapeutic induces side effects such as nephrotoxicity, so alternative therapies have been studied, such as the Annexin A1 protein (ANXA1), which exhibits anti-inflammatory, antiproliferative actions and also modulates expression of the Inhibitor of Differentiation to DNA 1 (ID1) gene in the tumor process. With these considerations, the objective of this work was to investigate the molecular interaction of the ANXA1 and ID1 mediators with Cis in cell line, and to relate with intraepithelial neoplastic tissues in the cervical tumorigenic process. SiHa (cervical epidermoid carcinoma) cells treated with the annexin A1 (AC2-26) peptide, Cis and AC2-26+ Cis, were evaluated in the proliferation, cytotoxicity, cell migration, apoptosis, immunolocalization and gene expression assays ANXA1 and ID1, and of the ANXA1, ID1 and ERK1/2 (Extracellular signalregulated kinase) proteins. Cervical tissue samples were analyzed histopathologically and the protein expression of ANXA1 and ID1 by immunohistochemistry. Treatments, in all groups, decreased cell proliferation and migration, without cytotoxic effects. While, Cis and AC2-26+ Cis induced the cells to processes of late apoptosis, decreased expression of ID1 and increased ANXA1, indicating the antineoplastic activity of cisplatin. Cis and AC2-26+ Cis administration inactivated ERK1/2 phosphorylated and induced nuclear translocation of ANXA1. Expressions of the ID1 and ANXA1 proteins were observed in tissue samples from Cervical Intraepithelial Neoplasia (CIN), with intense ID1 immunolabeling in CIN III. Together, the data obtained in this work provide additional understanding of the mechanism of action of cisplatin in the modulation of mediators ID1 and ANXA1 in the tumorigenic process. These findings may outline new strategies for therapeutic intervention in cervical cancer.
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Palavras-chave
Linhagem SiHa, Câncer de cérvice uterina, Apoptose, ID1, Translocação nuclear, SiHa line, Cancer of the uterine cervix, Apoptosis, Nuclear translocation