Article: article from journal or magazin.
Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression.
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.
Adaptor Proteins, Signal Transducing/metabolism, Animals, Autophagy/immunology, Cell Hypoxia/immunology, Cell Line, Tumor, Heat-Shock Proteins/metabolism, Humans, Lung Neoplasms/immunology, Lung Neoplasms/metabolism, Melanoma, Experimental/immunology, Melanoma, Experimental/metabolism, Mice, Mice, Inbred C57BL, Phosphorylation, Proteasome Endopeptidase Complex/metabolism, STAT3 Transcription Factor/metabolism, T-Lymphocytes, Cytotoxic/immunology, Ubiquitin/metabolism, src-Family Kinases/metabolism
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