title: Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities.
abstract: Inactivation of the Rb tumor suppressor can lead to increased cell proliferation or cell death depending on specific cellular context. Therefore, identification of the interacting pathways that modulate the effect of Rb loss will provide novel insights into the roles of Rb in cancer development and promote new therapeutic strategies. Here, we identify a novel synthetic lethal interaction between Rb inactivation and deregulated Wg/Wnt signaling through unbiased genetic screens. We show that a weak allele of axin, which deregulates Wg signaling and increases cell proliferation without obvious effects on cell fate specification, significantly alters metabolic gene expression, causes hypersensitivity to metabolic stress induced by fasting, and induces synergistic apoptosis with mutation of fly Rb ortholog, rbf. Furthermore, hyperactivation of Wg signaling by other components of the Wg pathway also induces synergistic apoptosis with rbf. We show that hyperactivated Wg signaling significantly increases TORC1 activity and induces excessive energy stress with rbf mutation. Inhibition of TORC1 activity significantly suppressed synergistic cell death induced by hyperactivated Wg signaling and rbf inactivation, which is correlated with decreased energy stress and decreased induction of apoptotic regulator expression. Finally the synthetic lethality between Rb and deregulated Wnt signaling is conserved in mammalian cells and that inactivation of Rb and APC induces synergistic cell death through a similar mechanism. These results suggest that elevated TORC1 activity and metabolic stress underpin the evolutionarily conserved synthetic lethal interaction between hyperactivated Wnt signaling and inactivated Rb tumor suppressor.
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, Texas, United States of America.
authors.forename: Fu-Ning
authors.initials: FN
authors.lastname: Hsu
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Robin
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Searle
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Xun
authors.initials: X
authors.lastname: Pei
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Hyung Don
authors.initials: HD
authors.lastname: Ryoo
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, Texas, United States of America.
authors.forename: Jun-Yuan
authors.initials: JY
authors.lastname: Ji
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers; D004330:Drosophila; D005804:Genes, Lethal; D016161:Genes, Retinoblastoma; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D046912:Multiprotein Complexes; D051153:Wnt Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases