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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH; v. 1833, n. 12, p. 2856-2865, DEC 2013.
• Web of Science Citations: 14

Abstract

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)

• FAPESP's process: 12/01038-9 - Lipid nanoparticles as a Co-Delivery system for genes and drugs: development, cellular processing and biological activity in cancer cells
• Grantee: Marcelo Bispo de Jesus
• Support Opportunities: Scholarships in Brazil - Post-Doctorate