TAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinom

Author(s):Show less -

Morelli, Ana Paula ^[1] ; Tortelli Jr, Tharcisio Citrangulo ; Silva Mancini, Mariana Camargo ^[1] ; Betim Pavan, Isadora Carolina ^{[1, 2]} ; Salvino Silva, Luiz Guilherme ^[1] ; Severino, Matheus Brandemarte ^[1] ; Granato, Daniela Campos ^[3] ; Pestana, Nathalie Fortes ^[1] ; Saboia Ponte, Luis Gustavo ^[1] ; Peruca, Guilherme Francisco ^[4] ; Pauletti, Bianca Alves ^[3] ; Guimaraes dos Santos Jr, Daniel Francisco ; de Moura, Leandro Pereira ^[4] ; Neves Bezerra, Rosangela Maria ^[5] ; Paes Leme, Adriana Franco ^[3] ; Chammas, Roger ^{[6, 7]} ; Simabuco, Fernando Moreira ^{[5, 4]}

Affiliation

^[1] Univ Estadual Campinas, Sch Appl Sci, Multidisciplinary Lab Food & Hlth, Limeira, SP - Brazil

^[2] Univ Estadual Campinas, Lab Signaling Mech, Sch Pharmaceut Sci, Campinas, SP - Brazil

^[3] Ctr Nacl Pesquisa Energia & Mat CNPEM, Lab Nacl Biociencias LNBio, Campinas, SP - Brazil

^[4] Univ Estadual Campinas, Sch Appl Sci, Exercise Cell Biol Lab, Limeira, SP - Brazil

^[5] Guimaraes dos Santos Jr, Jr., Daniel Francisco, Univ Estadual Campinas, Sch Appl Sci, Multidisciplinary Lab Food & Hlth, Limeira, SP - Brazil

^[6] Tortelli Jr, Jr., Tharcisio Citrangulo, Univ Sao Paulo, Ctr Invest Translac Oncol, Dept Radiol & Oncol, Fac Med, Sao Paulo, SP - Brazil

^[7] Tortelli Jr, Jr., Tharcisio Citrangulo, Inst Canc Estado de Sao Paulo, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Neoplasia; v. 23, n. 10, p. 1048-1058, OCT 2021.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 19/25582-9 - Study of the role of Nrf2 protein in metabolism regulation and redox control in response to natural food-derived compounds in Prostate Cancer cells
• Grantee: Mariana Camargo Silva Mancini
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 15/22814-5 - Cancer and heart: new paradigms of diagnosis and treatment
• Grantee: Carlos Eduardo Negrão
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/00311-1 - Functional characterization of interacting proteins of different S6Ks isoforms
• Grantee: Isadora Carolina Betim Pavan
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 18/14818-9 - Study of molecular targets important for the control of cancer metabolism: the mTOR/S6K pathway as a central role
• Grantee: Fernando Moreira Simabuco
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 19/00607-9 - Characterization of molecular targets involved in chemotherapeutic resistance and tumor metabolism of lung cancer cells
• Grantee: Ana Paula Morelli
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 20/09527-5 - SARS-CoV-2 Nsp9 protein in oxidative stress: nutraceuticals as a therapeutic approach
• Grantee: Luiz Guilherme Salvino da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate