Advanced

Myc-driven overgrowth requires unfolded protein response-mediated induction of autophagy and antioxidant responses in Drosophila melanogaster

Nagy, Péter; Varga, Agnes; Pircs, Karolina LU ; Hegedűs, Krisztina and Juhász, Gábor (2013) In PLoS Genetics 9(8). p.1-14
Abstract

Autophagy, a lysosomal self-degradation and recycling pathway, plays dual roles in tumorigenesis. Autophagy deficiency predisposes to cancer, at least in part, through accumulation of the selective autophagy cargo p62, leading to activation of antioxidant responses and tumor formation. While cell growth and autophagy are inversely regulated in most cells, elevated levels of autophagy are observed in many established tumors, presumably mediating survival of cancer cells. Still, the relationship of autophagy and oncogenic signaling is poorly characterized. Here we show that the evolutionarily conserved transcription factor Myc (dm), a proto-oncogene involved in cell growth and proliferation, is also a physiological regulator of autophagy... (More)

Autophagy, a lysosomal self-degradation and recycling pathway, plays dual roles in tumorigenesis. Autophagy deficiency predisposes to cancer, at least in part, through accumulation of the selective autophagy cargo p62, leading to activation of antioxidant responses and tumor formation. While cell growth and autophagy are inversely regulated in most cells, elevated levels of autophagy are observed in many established tumors, presumably mediating survival of cancer cells. Still, the relationship of autophagy and oncogenic signaling is poorly characterized. Here we show that the evolutionarily conserved transcription factor Myc (dm), a proto-oncogene involved in cell growth and proliferation, is also a physiological regulator of autophagy in Drosophila melanogaster. Loss of Myc activity in null mutants or in somatic clones of cells inhibits autophagy. Forced expression of Myc results in cell-autonomous increases in cell growth, autophagy induction, and p62 (Ref2P)-mediated activation of Nrf2 (cnc), a transcription factor promoting antioxidant responses. Mechanistically, Myc overexpression increases unfolded protein response (UPR), which leads to PERK-dependent autophagy induction and may be responsible for p62 accumulation. Genetic or pharmacological inhibition of UPR, autophagy or p62/Nrf2 signaling prevents Myc-induced overgrowth, while these pathways are dispensable for proper growth of control cells. In addition, we show that the autophagy and antioxidant pathways are required in parallel for excess cell growth driven by Myc. Deregulated expression of Myc drives tumor progression in most human cancers, and UPR and autophagy have been implicated in the survival of Myc-dependent cancer cells. Our data obtained in a complete animal show that UPR, autophagy and p62/Nrf2 signaling are required for Myc-dependent cell growth. These novel results give additional support for finding future approaches to specifically inhibit the growth of cancer cells addicted to oncogenic Myc.

(Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Antioxidant Response Elements, Autophagy, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Drosophila melanogaster, Gene Expression Regulation, Neoplastic, Humans, Mutation, NF-E2-Related Factor 2, Proto-Oncogene Proteins c-myc, Signal Transduction, Unfolded Protein Response, Journal Article, Research Support, Non-U.S. Gov't
in
PLoS Genetics
volume
9
issue
8
pages
1 - 14
publisher
Public Library of Science
external identifiers
  • scopus:84884636654
ISSN
1553-7404
DOI
10.1371/journal.pgen.1003664
language
English
LU publication?
no
id
887a2a80-fa8e-4029-9249-0b282c93e4bb
date added to LUP
2017-03-16 15:27:37
date last changed
2018-05-29 10:43:49
@article{887a2a80-fa8e-4029-9249-0b282c93e4bb,
  abstract     = {<p>Autophagy, a lysosomal self-degradation and recycling pathway, plays dual roles in tumorigenesis. Autophagy deficiency predisposes to cancer, at least in part, through accumulation of the selective autophagy cargo p62, leading to activation of antioxidant responses and tumor formation. While cell growth and autophagy are inversely regulated in most cells, elevated levels of autophagy are observed in many established tumors, presumably mediating survival of cancer cells. Still, the relationship of autophagy and oncogenic signaling is poorly characterized. Here we show that the evolutionarily conserved transcription factor Myc (dm), a proto-oncogene involved in cell growth and proliferation, is also a physiological regulator of autophagy in Drosophila melanogaster. Loss of Myc activity in null mutants or in somatic clones of cells inhibits autophagy. Forced expression of Myc results in cell-autonomous increases in cell growth, autophagy induction, and p62 (Ref2P)-mediated activation of Nrf2 (cnc), a transcription factor promoting antioxidant responses. Mechanistically, Myc overexpression increases unfolded protein response (UPR), which leads to PERK-dependent autophagy induction and may be responsible for p62 accumulation. Genetic or pharmacological inhibition of UPR, autophagy or p62/Nrf2 signaling prevents Myc-induced overgrowth, while these pathways are dispensable for proper growth of control cells. In addition, we show that the autophagy and antioxidant pathways are required in parallel for excess cell growth driven by Myc. Deregulated expression of Myc drives tumor progression in most human cancers, and UPR and autophagy have been implicated in the survival of Myc-dependent cancer cells. Our data obtained in a complete animal show that UPR, autophagy and p62/Nrf2 signaling are required for Myc-dependent cell growth. These novel results give additional support for finding future approaches to specifically inhibit the growth of cancer cells addicted to oncogenic Myc.</p>},
  articleno    = {e1003664},
  author       = {Nagy, Péter and Varga, Agnes and Pircs, Karolina and Hegedűs, Krisztina and Juhász, Gábor},
  issn         = {1553-7404},
  keyword      = {Animals,Antioxidant Response Elements,Autophagy,Carcinogenesis,Cell Line, Tumor,Cell Proliferation,Drosophila melanogaster,Gene Expression Regulation, Neoplastic,Humans,Mutation,NF-E2-Related Factor 2,Proto-Oncogene Proteins c-myc,Signal Transduction,Unfolded Protein Response,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {8},
  pages        = {1--14},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Myc-driven overgrowth requires unfolded protein response-mediated induction of autophagy and antioxidant responses in Drosophila melanogaster},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1003664},
  volume       = {9},
  year         = {2013},
}