p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors

Alessandro Sgambato, Giannicola Genovese, Alessandro Carugo, Rosalba Minelli, Luigi Sapio, Melinda Soeung, Federica Carbone, Frederick S. Robinson, James Tepper, Ziheng Chen, Sara Lovisa, Maria Svelto, Samirkumar Amin, Sanjana Srinivasan, Edoardo Del Poggetto, Sara Loponte, Francesca Puca, Prasenjit Dey, Gabriel G. Malouf, Xiaoping SuLiren Li, Dolores Lopez-Terrada, Dinesh Rakheja, Alexander J. Lazar, George J. Netto, Priya Rao, Anirban Maitra, Durga N. Tripathi, Cheryl L. Walker, Jose A. Karam, Timothy P. Heffernan, Andrea Viale, Charles W.M. Roberts, Pavlos Msaouel, Nizar M. Tannir, Giulio F. Draetta

Risultato della ricerca: Contributo in rivistaArticolo in rivista

19 Citazioni (Scopus)

Abstract

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19 ARF -p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.
Lingua originaleEnglish
pagine (da-a)204-220.e9
RivistaCancer Cell
Volume35
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • autophagy
  • Proteostasis
  • embryonic mosaic GEM models
  • ER stress
  • MYC
  • p53
  • proteasome inhibitors
  • renal medullary carcinoma
  • rhabdoid tumors
  • SMARCB1
  • Animals
  • Antineoplastic Agents
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Rhabdoid Tumor
  • SMARCB1 Protein
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53
  • Unfolded Protein Response
  • Autophagy
  • Endoplasmic Reticulum Stress
  • BIRC5

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