STAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinoma
Lung cancer is the second leading cause of cancer death worldwide and is strongly associated with cisplatin resistance. The transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer cells and coordinates critical cellular processes as survi...
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Elsevier
2021-10-01
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Series: | Neoplasia: An International Journal for Oncology Research |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558621000683 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ana Paula Morelli Tharcísio Citrângulo Tortelli, Jr Mariana Camargo Silva Mancini Isadora Carolina Betim Pavan Luiz Guilherme Salvino Silva Matheus Brandemarte Severino Daniela Campos Granato Nathalie Fortes Pestana Luis Gustavo Saboia Ponte Guilherme Francisco Peruca Bianca Alves Pauletti Daniel Francisco Guimarães dos Santos, Jr Leandro Pereira de Moura Rosângela Maria Neves Bezerra Adriana Franco Paes Leme Roger Chammas Fernando Moreira Simabuco |
spellingShingle |
Ana Paula Morelli Tharcísio Citrângulo Tortelli, Jr Mariana Camargo Silva Mancini Isadora Carolina Betim Pavan Luiz Guilherme Salvino Silva Matheus Brandemarte Severino Daniela Campos Granato Nathalie Fortes Pestana Luis Gustavo Saboia Ponte Guilherme Francisco Peruca Bianca Alves Pauletti Daniel Francisco Guimarães dos Santos, Jr Leandro Pereira de Moura Rosângela Maria Neves Bezerra Adriana Franco Paes Leme Roger Chammas Fernando Moreira Simabuco STAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinoma Neoplasia: An International Journal for Oncology Research Lung cancer Cisplatin Proteomics STAT3 mTOR Rapamycin |
author_facet |
Ana Paula Morelli Tharcísio Citrângulo Tortelli, Jr Mariana Camargo Silva Mancini Isadora Carolina Betim Pavan Luiz Guilherme Salvino Silva Matheus Brandemarte Severino Daniela Campos Granato Nathalie Fortes Pestana Luis Gustavo Saboia Ponte Guilherme Francisco Peruca Bianca Alves Pauletti Daniel Francisco Guimarães dos Santos, Jr Leandro Pereira de Moura Rosângela Maria Neves Bezerra Adriana Franco Paes Leme Roger Chammas Fernando Moreira Simabuco |
author_sort |
Ana Paula Morelli |
title |
STAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinoma |
title_short |
STAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinoma |
title_full |
STAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinoma |
title_fullStr |
STAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinoma |
title_full_unstemmed |
STAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinoma |
title_sort |
stat3 contributes to cisplatin resistance, modulating emt markers, and the mtor signaling in lung adenocarcinoma |
publisher |
Elsevier |
series |
Neoplasia: An International Journal for Oncology Research |
issn |
1476-5586 |
publishDate |
2021-10-01 |
description |
Lung cancer is the second leading cause of cancer death worldwide and is strongly associated with cisplatin resistance. The transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer cells and coordinates critical cellular processes as survival, self-renewal, and inflammation. In several types of cancer, STAT3 controls the development, immunogenicity, and malignant behavior of tumor cells while it dictates the responsiveness to radio- and chemotherapy. It is known that STAT3 phosphorylation at Ser727 by mechanistic target of rapamycin (mTOR) is necessary for its maximal activation, but the crosstalk between STAT3 and mTOR signaling in cisplatin resistance remains elusive. In this study, using a proteomic approach, we revealed important targets and signaling pathways altered in cisplatin-resistant A549 lung adenocarcinoma cells. STAT3 had increased expression in a resistance context, which can be associated with a poor prognosis. STAT3 knockout (SKO) resulted in a decreased mesenchymal phenotype in A549 cells, observed by clonogenic potential and by the expression of epithelial-mesenchymal transition markers. Importantly, SKO cells did not acquire the mTOR pathway overactivation induced by cisplatin resistance. Consistently, SKO cells were more responsive to mTOR inhibition by rapamycin and presented impairment of the feedback activation loop in Akt. Therefore, rapamycin was even more potent in inhibiting the clonogenic potential in SKO cells and sensitized to cisplatin treatment. Mechanistically, STAT3 partially coordinated the cisplatin resistance phenotype via the mTOR pathway in non-small cell lung cancer. Thus, our findings reveal important targets and highlight the significance of the crosstalk between STAT3 and mTOR signaling in cisplatin resistance. The synergic inhibition of STAT3 and mTOR potentially unveil a potential mechanism of synthetic lethality to be explored for human lung cancer treatment. |
topic |
Lung cancer Cisplatin Proteomics STAT3 mTOR Rapamycin |
url |
http://www.sciencedirect.com/science/article/pii/S1476558621000683 |
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doaj-1217d0e2aea84eb8973ce862d6ac0a742021-09-25T05:05:46ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862021-10-01231010481058STAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinomaAna Paula Morelli0Tharcísio Citrângulo Tortelli, Jr1Mariana Camargo Silva Mancini2Isadora Carolina Betim Pavan3Luiz Guilherme Salvino Silva4Matheus Brandemarte Severino5Daniela Campos Granato6Nathalie Fortes Pestana7Luis Gustavo Saboia Ponte8Guilherme Francisco Peruca9Bianca Alves Pauletti10Daniel Francisco Guimarães dos Santos, Jr11Leandro Pereira de Moura12Rosângela Maria Neves Bezerra13Adriana Franco Paes Leme14Roger Chammas15Fernando Moreira Simabuco16Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP, BrazilCentro de Investigação Translacional em Oncologia, Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP, BrazilMultidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP, BrazilMultidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP, Brazil; Laboratory of Signaling Mechanisms, School of Pharmaceutical Sciences, State University of Campinas, Campinas, SP, BrazilMultidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP, BrazilMultidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP, BrazilLaboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, BrazilMultidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP, BrazilMultidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP, BrazilExercise Cell Biology Laboratory, School of Applied Sciences, State University of Campinas, Limeira, SP, BrazilLaboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, BrazilMultidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP, BrazilExercise Cell Biology Laboratory, School of Applied Sciences, State University of Campinas, Limeira, SP, BrazilMultidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP, BrazilLaboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, BrazilCentro de Investigação Translacional em Oncologia, Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP, BrazilMultidisciplinary Laboratory of Food and Health, School of Applied Sciences, State University of Campinas, Limeira, SP, Brazil; Corresponding author.Lung cancer is the second leading cause of cancer death worldwide and is strongly associated with cisplatin resistance. The transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer cells and coordinates critical cellular processes as survival, self-renewal, and inflammation. In several types of cancer, STAT3 controls the development, immunogenicity, and malignant behavior of tumor cells while it dictates the responsiveness to radio- and chemotherapy. It is known that STAT3 phosphorylation at Ser727 by mechanistic target of rapamycin (mTOR) is necessary for its maximal activation, but the crosstalk between STAT3 and mTOR signaling in cisplatin resistance remains elusive. In this study, using a proteomic approach, we revealed important targets and signaling pathways altered in cisplatin-resistant A549 lung adenocarcinoma cells. STAT3 had increased expression in a resistance context, which can be associated with a poor prognosis. STAT3 knockout (SKO) resulted in a decreased mesenchymal phenotype in A549 cells, observed by clonogenic potential and by the expression of epithelial-mesenchymal transition markers. Importantly, SKO cells did not acquire the mTOR pathway overactivation induced by cisplatin resistance. Consistently, SKO cells were more responsive to mTOR inhibition by rapamycin and presented impairment of the feedback activation loop in Akt. Therefore, rapamycin was even more potent in inhibiting the clonogenic potential in SKO cells and sensitized to cisplatin treatment. Mechanistically, STAT3 partially coordinated the cisplatin resistance phenotype via the mTOR pathway in non-small cell lung cancer. Thus, our findings reveal important targets and highlight the significance of the crosstalk between STAT3 and mTOR signaling in cisplatin resistance. The synergic inhibition of STAT3 and mTOR potentially unveil a potential mechanism of synthetic lethality to be explored for human lung cancer treatment.http://www.sciencedirect.com/science/article/pii/S1476558621000683Lung cancerCisplatinProteomicsSTAT3mTORRapamycin |