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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• 作者：Karin Juliane Pelizzaro-Rocha ; Marcelo Bispo de Jesus ; Roberta Regina Ruela-de-Sousa ; Celso Vataru Nakamura ; Fabiano Souza Reis ; Angelo de F谩tima ; Carmen Ver铆ssima Ferreira-Halder
• 关键词：CLX6 ; Calix[6]arene ; CDKs ; cyclin-dependent kinases ; RB ; retinoblastoma ; PIM ; proviral integration site for the moloney murine leukemia virus ; AXL ; tyrosine-protein kinase receptor UFO ; Mer ; tyrosine-protein kinase receptor ; PI3K ; phosphoinositide 3-kinase ; AKT ; a serine/threonine-specific protein kinase ; also known as Protein Kinase B (PKB) ; mTOR ; mammalian target of rapamycin ; a Serine/Threonine protein kinase ; BAX ; BCL2-associated X protein ; BCL2 ; B-cell lymphoma protein-2 ; LC3 ; microtubule-a
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：December, 2013
• 年：2013
• 卷：1833
• 期：12
• 页码：2856-2865
• 全文大小：1813 K

文摘

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-伪 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.