Abstract
BackgoundAutophagy controls levels of cellular components during normal and stress conditions; thus, it is a pivotal process for the maintenance of cell homeostasis. In cancer, autophagy protects cells from cancerous transformations that can result from genomic instability induced by reactive oxygen species or other damaged components, but it can also promote cancer survival by providing essential nutrients during the metabolic stress condition of cancer progression. However, the molecular mechanism underlying autophagy-dependent regulation of the epithelial to mesenchymal transition (EMT) and metastasis is still elusive.MethodsThe intracellular level of NOTCH1 intracellular domain (NICD) in several cancer cells was studied under starvation, treatment with chloroquine or ATG7-knockdown. The autophagy activity in these cells was assessed by immunocytochemistry and molecular analyses. Cancer cell migration and invasion under modulation of autophagy were determined by in vitro scratch and Matrigel assays.ResultsIn the study, autophagy activation stimulated degradation of NICD, a key transcriptional regulator of the EMT and cancer metastasis. We also found that NICD binds directly to LC3 and that the NICD/LC3 complex associates with SNAI1 and sequestosome 1 (SQSTM1)/p62 proteins. Furthermore, the ATG7 knockdown significantly inhibited degradation of NICD under starvation independent of SQSTM1-associated proteasomal degradation. In addition, NICD degradation by autophagy associated with the cellular level of SNAI1. Indeed, autophagy inhibited nuclear translocation of NICD protein and consequently decreased the transcriptional activity of its target genes. Autophagy activation substantially suppressed in vitro cancer cell migration and invasion. We also observed that NICD and SNAI1 levels in tissues from human cervical and lung cancer patients correlated inversely with expression of autophagy-related proteins.ConclusionsThese findings suggest that the cellular level of NICD is regulated by autophagy during cancer progression and that targeting autophagy-dependent NICD/SNAI1 degradation could be a strategy for the development of cancer therapeutics.
Highlights
Autophagy is a catabolic process in which intracellular proteins and organelles are engulfed into double membrane autophagosomes and subsequently fused with lysosomes for degradation
Autophagy promotes NOTCH1 intracellular domain (NICD) degradation in cancer cells Notch signaling plays a critical role in cell development and differentiation and in control of the epithelial to mesenchymal transition (EMT) and cancer metastasis [14, 25, 31]
To elucidate whether autophagy modulates the intracellular level of NICD, the transcriptional activator domain of NOTCH1, we examined the cellular level of NICD in several cancer cells upon induction of autophagy by starvation or rapamycin treatment
Summary
Autophagy is a catabolic process in which intracellular proteins and organelles are engulfed into double membrane autophagosomes and subsequently fused with lysosomes for degradation. This phenomenon occurs intrinsically to support cell survival in metabolically deficient microenvironments [1,2,3]. Autophagy plays a context-dependent role in tumorigenesis as a tumor suppressor or a tumor promoter. Autophagy promotes cancer cell survival during unfavorable metabolic conditions by supplying essential nutrients through the self-eating process [4, 5]. The role of autophagy in cancer progression is still debatable
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have