title: Calix[6]arene bypasses human pancreatic cancer aggressiveness: downregulation of receptor tyrosine kinases and induction of cell death by reticulum stress and autophagy.
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 AKT at Thr308, calix[6]arene caused an increase in phosphorylation at Ser473. These findings in conjunction with increased BiP and IRE1-α 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.
authors.affiliation: Department of Biochemistry, Biology Institute, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Karin Juliane
authors.initials: KJ
authors.lastname: Pelizzaro-Rocha
authors.affiliation: Department of Biochemistry, Biology Institute, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Marcelo Bispo
authors.initials: MB
authors.lastname: de Jesus
authors.affiliation: Department of Biochemistry, Biology Institute, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Roberta Regina
authors.initials: RR
authors.lastname: Ruela-de-Sousa
authors.affiliation: Department of Basic Health Sciences, State University of Maringá, Maringá, Paraná, Brazil.
authors.forename: Celso Vataru
authors.initials: CV
authors.lastname: Nakamura
authors.affiliation: Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Fabiano Souza
authors.initials: FS
authors.lastname: Reis
authors.affiliation: Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Angelo
authors.initials: A
authors.lastname: de Fátima
authors.affiliation: Department of Biochemistry, Biology Institute, University of Campinas, Campinas, São Paulo, Brazil. Electronic address: carmenv@unicamp.br.
authors.forename: Carmen Veríssima
authors.initials: CV
authors.lastname: Ferreira-Halder
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D047250:Calixarenes / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D047250:Calixarenes; D002738:Chloroquine; D010636:Phenols; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C476540:calix(6)arene
keywords: AKT; AXL; Autophagy; B-cell lymphoma protein-2; BAX; BCL2; BCL2-associated X protein; BiP; CDKs; CLQ; CLX6; CTRL; Calix[6]arene; ER; Endoplasmic reticulum stress; HSP90; IRE1; JNK2; LC3; Mer; PI3K; PIM; Pancreatic cancer; RB; Receptor tyrosine kinase; a serine/threonine-specific protein kinase, also known as Protein Kinase B (PKB); binding immunoglobulin protein; c-Jun N-terminal protein kinase 2; chloroquine; control; cyclin-dependent kinases; endoplasmic reticulum; heat shock protein 90; inositol-requiring protein 1, a serine/threonine protein kinase/endoribonuclease; mTOR; mammalian target of rapamycin, a Serine/Threonine protein kinase; microtubule-associated protein light chain 3; phosphoinositide 3-kinase; proviral integration site for the moloney murine leukemia virus; retinoblastoma; tyrosine-protein kinase receptor; tyrosine-protein kinase receptor UFO