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.
The evolutionarily conserved transcription factor Myc promotes protein synthesis, cell growth and cancer progression through incompletely understood mechanisms. In this work, we show that forced expression of Myc induces the accumulation of abnormal proteins leading to unfolded protein responses (UPR), presumably by overloading the protein synthetic capacity of cells in Drosophila. UPR then results in autophagy-mediated breakdown and recycling of cytoplasmic material, and at the same time, to activation of antioxidant responses in these cells. Blocking the UPR stress signaling, autophagy and antioxidant pathways genetically, or by feeding larvae an autophagy-inhibiting drug, prevents overgrowth of Myc-expressing cells, but these treatments do not affect the growth of control cells in the same tissues. These results, together with recent reports in mammalian cancer models, suggest that drugs targeting UPR, autophagy and antioxidant responses may specifically inhibit cancer cell proliferation driven by oncogenic Myc.