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Title: Autophagy contributes to gefitinib-induced glioma cell growth inhibition

Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, have been evaluated in patients with malignant gliomas. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma are incompletely understood. In the present study, the cytostatic potential of gefitinib was demonstrated by the inhibition of glioma cell growth, long-term clonogenic survival, and xenograft tumor growth. The cytostatic consequences were accompanied by autophagy, as evidenced by monodansylcadaverine staining of acidic vesicle formation, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), degradation of p62, punctate pattern of GFP-LC3, and conversion of GFP-LC3 to cleaved-GFP. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 or Beclin 1 attenuated gefitinib-induced growth inhibition. Gefitinib-induced autophagy was not accompanied by the disruption of the Akt/mammalian target of rapamycin signaling. Instead, the activation of liver kinase-B1/AMP-activated protein kinase (AMPK) signaling correlated well with the induction of autophagy and growth inhibition caused by gefitinib. Silencing of AMPK suppressed gefitinib-induced autophagy and growth inhibition. The crucial role of AMPK activation in inducing glioma autophagy and growth inhibition was further supported by the actions of AMP mimetic AICAR. Gefitinib was shown to be capable of reducing the proliferation of glioma cells, presumably by autophagic mechanisms involving AMPK activation.more » - Highlights: • Gefitinib causes cytotoxic and cytostatic effect on glioma. • Gefitinib induces autophagy. • Gefitinib causes cytostatic effect through autophagy. • Gefitinib induces autophagy involving AMPK.« less
Authors:
 [1] ;  [2] ;  [3] ;  [2] ; ;  [4] ;  [5] ;  [2] ;  [6] ;  [7] ;  [1] ;  [8] ;  [2] ;  [2] ;  [2] ;  [2]
  1. Department of Surgery, Fong-Yuan Hospital, Taichung 420, Taiwan (China)
  2. (China)
  3. Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan (China)
  4. Division of Urology, Taichung Veterans General Hospital, Taichung 407, Taiwan (China)
  5. Department of Anesthesiology, Taichung Veterans General Hospital, Taichung 407, Taiwan (China)
  6. Department of Pediatrics, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan (China)
  7. Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan (China)
  8. Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan (China)
Publication Date:
OSTI Identifier:
22416928
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 327; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMP; CELL PROLIFERATION; GLIOMAS; GROWTH FACTORS; INHIBITION; LIVER; MICROTUBULES; PLANT GROWTH; RECEPTORS; SIGNALS; TYROSINE