HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression.

Abstract
The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)-mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.
AuthorsMuhammad Zaeem Noman, Bassam Janji, Bozena Kaminska, Kris Van Moer, Sandrine Pierson, Piotr Przanowski, Stéphanie Buart, Guy Berchem, Pedro Romero, Fathia Mami-Chouaib, Salem Chouaib
JournalCancer research (Cancer Res) Vol. 71 Issue 18 Pg. 5976-86 (Sep 15 2011) ISSN: 1538-7445 [Electronic] United States
PMID21810913 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Heat-Shock Proteins
  • SQSTM1 protein, human
  • STAT3 Transcription Factor
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Ubiquitin
  • src-Family Kinases
  • Proteasome Endopeptidase Complex
Topics
  • Adaptor Proteins, Signal Transducing (metabolism)
  • Animals
  • Autophagy (immunology)
  • Cell Hypoxia (immunology)
  • Cell Line, Tumor
  • Heat-Shock Proteins (metabolism)
  • Humans
  • Lung Neoplasms (immunology, metabolism, pathology)
  • Melanoma, Experimental (immunology, metabolism, pathology)
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Proteasome Endopeptidase Complex (metabolism)
  • STAT3 Transcription Factor (metabolism)
  • Sequestosome-1 Protein
  • T-Lymphocytes, Cytotoxic (immunology)
  • Ubiquitin (metabolism)
  • src-Family Kinases (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: