Title: Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma.
Authors: Tsang, Tiffany; Posimo, Jessica M; Gudiel, Andrea A; Cicchini, Michelle; Feldser, David M; Brady, Donita C
Published In Nat Cell Biol, (2020 04)
Abstract: Although the transition metal copper (Cu) is an essential nutrient that is conventionally viewed as a static cofactor within enzyme active sites, a non-traditional role for Cu as a modulator of kinase signalling is emerging. Here, we found that Cu is required for the activity of the autophagic kinases ULK1 and ULK2 (ULK1/2) through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt the binding of Cu reduced ULK1/2-dependent signalling and the formation of autophagosome complexes. Increased levels of intracellular Cu are associated with starvation-induced autophagy and are sufficient to enhance ULK1 kinase activity and, in turn, autophagic flux. The growth and survival of lung tumours driven by KRASG12D is diminished in the absence of Ctr1, is dependent on ULK1 Cu binding and is associated with reduced levels of autophagy and signalling. These findings suggest a molecular basis for exploiting Cu-chelation therapy to prevent autophagy signalling to limit proliferation and improve patient survival in cancer.
PubMed ID: 32203415
MeSH Terms: Adenocarcinoma of Lung/enzymology; Adenocarcinoma of Lung/genetics*; Adenocarcinoma of Lung/pathology; Amino Acid Sequence; Animals; Autophagosomes/enzymology; Autophagy-Related Protein 5/deficiency; Autophagy-Related Protein 5/genetics; Autophagy-Related Protein-1 Homolog/genetics*; Autophagy-Related Protein-1 Homolog/metabolism; Autophagy/genetics*; Cell Line, Tumor; Cell Proliferation; Cell Survival; Copper Transporter 1/deficiency; Copper Transporter 1/genetics; Copper/metabolism*; Fibroblasts/enzymology; Fibroblasts/pathology; Gene Expression Regulation, Neoplastic*; Humans; Intracellular Signaling Peptides and Proteins/genetics*; Intracellular Signaling Peptides and Proteins/metabolism; Lung Neoplasms/enzymology; Lung Neoplasms/genetics*; Lung Neoplasms/pathology; Mice; Mice, Knockout; Protein-Serine-Threonine Kinases/genetics*; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins p21(ras)/deficiency; Proto-Oncogene Proteins p21(ras)/genetics; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction; Xenograft Model Antitumor Assays