Abstract
Autophagy is an evolutionarily conserved lysosomal degradation pathway that plays an essential role in enabling eukaryotic organisms to adapt to nutrient deprivation and other forms of environmental stress. In metazoan organisms, autophagy is essential for differentiation and normal development; however, whether the autophagy pathway promotes or inhibits tumorigenesis is controversial, and the possible mechanisms linking defective autophagy to cancer remain unclear. To determine if autophagy is important for tumor suppression, we inhibited autophagy in transgenic zebrafish via stable, tissue-specific expression of a dominant-negative autophagy protein Atg5K130R. In heterozygous tp53 mutants, expression of dominant-negative atg5K130R increased tumor incidence and decreased tumor latency compared to non-transgenic heterozygous tp53 mutant controls. In a tp53-deficient background, Tg(mitfa:atg5K130R) mutantsdeveloped malignant peripheral nerve sheath tumors (MPNSTs), neuroendocrine tumors and small-cell tumors. Expression of a Sox10-dependent GFP transgene in the tumors demonstrated their origin from neural crest cells, lending support to a model in which mitfa-expressing cells can arise from sox10+ Schwann cell precursors. Tumors from the transgenic animals exhibited increased DNA damage and loss-of-heterozygosity of tp53. Taken together, our data indicate that genetic inhibition of autophagy promotes tumorigenesis in tp53 mutant zebrafish, and suggest a possible role for autophagy in the regulation of genome stability during oncogenesis.
Highlights
Autophagy is a highly conserved cellular degradation pathway that mediates the degradation of macromolecules and organelles by the lysosome [1]
We injected mRNA encoding mCherry, zebrafish atg5 or dominant-negative atg5K130R mRNA, or a morpholino directed against atg5 that we previously validated [33] into one-cell stage Tg(CMV:GFP-Lc3) embryos
There is ongoing controversy regarding the role of autophagy in tumorigenesis
Summary
Autophagy is a highly conserved cellular degradation pathway that mediates the degradation of macromolecules and organelles by the lysosome [1]. Autophagy exerts a quality control function by removing misfolded or unfolded proteins and damaged organelles In light of these many important functions, it is not surprising that autophagy plays an essential role in normal physiology and protection against diseases, including neurodegenerative diseases, infection and aging [2, 3]. The anticancer effects of tumor-suppressor genes such as PTEN, LKB1 and TSC1/TSC2 derive, at least in part, from their regulation of PI3K-mTOR signaling, which normally opposes the autophagy pathway. Consistent with this idea, oncogenes such as AKT, EGFR and BCL2 may promote tumorigenesis by inhibiting autophagy, either through a positive effect on mTOR signaling (reviewed in [13]) or directly via effects on Beclin 1 [14,15,16]
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