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Cited by 24PI3K/AKT/mTOR signaling in cancerLung Cancer Treatments and MutationsCytokine Signaling Pathways and Interactions

STAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinoma

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Morelli, Ana Paula, Tortelli, Tharcísio Citrângulo, Mancini, Mariana Camargo Silva, Pavan, Isadora Carolina Betim, Silva, Luiz Guilherme Salvino, Severino, Matheus Brandemarte, Granato, Daniela Campos, Pestana, Nathalie Fortes +9 more·2021·Neoplasia
DOI 10.1016/j.neo.2021.08.003PMC PMC8453219
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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.

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Authors
Morelli, A. P., Tortelli, T. C., Mancini, M. C. S., Pavan, I. C. B., Silva, L. G. S., Severino, M. B., Granato, D. C., Pestana, N. F., Ponte, L. G. S., Peruca, G. F., Pauletti, B. A., dos Santos, D. F. G., de Moura, L. P., Bezerra, R. M. N., Leme, A. F. P., Chammas, R., & Simabuco, F. M.
Affiliations
  • Universidade Estadual de Campinas (UNICAMP) (BR)
  • Universidade de São Paulo (BR)
  • Brazilian Center for Research in Energy and Materials (BR)
Corresponding author
Simabuco, Fernando Moreira
ORCID
Venue
Neoplasia
Publisher
Elsevier BV
Published
2021-10
Volume
23
Issue
10
Pages
1048-1058
ISSN
1476-5586 (ISSN-L)
DOI
10.1016/j.neo.2021.08.003
PMC
PMC8453219
OpenAlex
W3199268645
Cited by
24
References
66
Citations by year
2026: 7 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 4
FWCI
0.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Neoplasia (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2015/00311-1, 2015/22814-5, 2018/14818-9, 2019/00607‐9, 2019/25582-9, 2020/09527-5)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (447553/2014-3)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
STAT3, cisplatin resistance, lung adenocarcinoma, epithelial-mesenchymal transition, mTOR signaling, rapamycin, A549 cells, clonogenicity, synthetic lethality, non-small cell lung cancer

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