title: p62/SQSTM1 synergizes with autophagy for tumor growth in vivo.
abstract: Autophagy is crucial for cellular homeostasis and plays important roles in tumorigenesis. FIP200 (FAK family-interacting protein of 200 kDa) is an essential autophagy gene required for autophagy induction, functioning in the ULK1-ATG13-FIP200 complex. Our previous studies showed that conditional knockout of FIP200 significantly suppressed mammary tumorigenesis, which was accompanied by accumulation of p62 in tumor cells. However, it is not clear whether FIP200 is also required for maintaining tumor growth and how the increased p62 level affects the growth in autophagy-deficient FIP200-null tumors in vivo. Here, we describe a new system to delete FIP200 in transformed mouse embryonic fibroblasts as well as mammary tumor cells following their transplantation and show that ablation of FIP200 significantly reduced growth of established tumors in vivo. Using similar strategies, we further showed that either p62 knockdown or p62 deficiency in established FIP200-null tumors dramatically impaired tumor growth. The stimulation of tumor growth by p62 accumulation in FIP200-null tumors is associated with the up-regulated activation of the NF-κB pathway by p62. Last, we showed that overexpression of the autophagy master regulator TFEB(S142A) increased the growth of established tumors, which correlated with the increased autophagy of the tumor cells. Together, our studies demonstrate that p62 and autophagy synergize to promote tumor growth, suggesting that inhibition of both pathways could be more effective than targeting either alone for cancer therapy.
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA;
authors.forename: Huijun
authors.initials: H
authors.lastname: Wei
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Chenran
authors.initials: C
authors.lastname: Wang
authors.affiliation: Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA;
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D001943:Breast Neoplasms / Q000235:genetics / Q000503:physiopathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; C428743:Rb1cc1 protein, mouse; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse
keywords: autophagy; mouse models; p62; tumor growth