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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Calix[6]arene bypasses human pancreatic cancer aggressiveness: Downregulation of receptor tyrosine kinases and induction of cell death by reticulum stress and autophagy

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Autor(es):
Pelizzaro-Rocha, Karin Juliane [1] ; de Jesus, Marcelo Bispo [1] ; Ruela-de-Sousa, Roberta Regina [1] ; Nakamura, Celso Vataru [2] ; Reis, Fabiano Souza [3] ; de Fatima, Angelo [3] ; Ferreira-Halder, Carmen Verissima [1]
Número total de Autores: 7
Afiliação do(s) autor(es):
[1] Univ Estadual Campinas, Inst Biol, Dept Biochem, Campinas, SP - Brazil
[2] Univ Estadual Maringa, Dept Basic Hlth Sci, Maringa, Parana - Brazil
[3] Univ Fed Minas Gerais, Dept Chem, Belo Horizonte, MG - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH; v. 1833, n. 12, p. 2856-2865, DEC 2013.
Citações Web of Science: 14
Resumo

Pancreatic cancer ranks fourth among cancer-related causes of death in North America. Minimal progress has been made in the diagnosis and treatment of patients with late-stage tumors. Moreover, pancreatic cancer aggressiveness is closely related to high levels of pro-survival mediators, which can ultimately lead to rapid disease progression, resistance and metastasis. The main goal of this study was to define the mechanisms by which calix{[}6]arene, but not other calixarenes, efficiently decreases the aggressiveness of a drug resistant human pancreas carcinoma cell line (Panc-1). Calix{[}6]arene was more potent in reducing Panc-1 cell viability than gemcitabine and 5-fluorouracil. In relation to the underlying mechanisms of cytotoxic effects, it led to cell cycle arrest in the G0/G1 phase through downregulation of PIM1, CDK2, CDK4 and retinoblastoma proteins. Importantly, calix{[}6]arene abolished signal transduction of Mer and AXL tyrosine kinase receptors, both of which are usually overexpressed in pancreatic cancer. Accordingly, inhibition of PI3K and mTOR was also observed, and these proteins are positively modulated by Mer and AXL, Despite decreasing the phosphorylation of ART at Thr308, calix{[}6]arene caused an increase in phosphorylation at Ser473. These findings in conjunction with increased BiP and IRE1-alpha provide a molecular basis explaining the capacity of calix{[}6{[}arene to trigger endoplasmic reticulum stress and autophagic cell death. Our findings highlight calix{[}6]arene as a potential candidate for overcoming pancreatic cancer aggressiveness. Importantly, we provide evidence that calix{[}6]arene affects a broad array of key targets that are usually dysfunctional in pancreatic cancer, a highly desirable characteristic for chemotherapeutics. (C) 2013 Elsevier B.V. All rights reserved. (AU)

Processo FAPESP: 08/57906-3 - Instituto Nacional de Fotônica Aplicada à Biologia Celular - INFABIC
Beneficiário:Hernandes Faustino de Carvalho
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 12/01038-9 - Nanopartículas lipídicas como carreadoras de fármacos e genes: desenvolvimento, tracking do processamento intracelular e atividade biológica em células de câncer
Beneficiário:Marcelo Bispo de Jesus
Linha de fomento: Bolsas no Brasil - Pós-Doutorado