title: β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer.
abstract: The Wnt–β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer. AKT phosporylates FOXO3a, relocating it from the cell nucleus to the cytoplasm, an effect that is reversed by PI3K and AKT inhibitors. Simultaneous hyperactivation of the Wnt–β-catenin pathway and inhibition of PI3K-AKT signaling promote nuclear accumulation of β-catenin and FOXO3a, respectively, promoting cell scattering and metastasis by regulating a defined set of target genes. Indeed, the anti-tumoral AKT inhibitor API-2 promotes nuclear FOXO3a accumulation and metastasis of cells with high nuclear β-catenin content. Nuclear β-catenin confers resistance to the FOXO3a-mediated apoptosis induced by PI3K and AKT inhibitors in patient-derived primary cultures and in corresponding xenograft tumors in mice. This resistance is reversed by XAV-939, an inhibitor of Wnt–β-catenin signaling. In the presence of high nuclear β-catenin content, activation of FOXO3a by PI3K or AKT inhibitors makes it behave as a metastasis inductor rather than a proapoptotic tumor suppressor. We show that it is possible to evaluate the β-catenin status of patients' carcinomas and the response of patient-derived cells to target-directed drugs that accumulate FOXO3a in the nucleus before deciding on a course of treatment. We propose that this evaluation could be essential to the provision of a safer and more effective personalized treatment.
authors.affiliation: Vall d’Hebrón Institut d’Oncología (VHIO), Stem Cell and Cancer Laboratory, Barcelona, Spain.
authors.forename: Stephan P
authors.initials: SP
authors.lastname: Tenbaum
authors.forename: Paloma
authors.initials: P
authors.lastname: Ordóñez-Morán
authors.forename: Isabel
authors.initials: I
authors.lastname: Puig
authors.forename: Irene
authors.initials: I
authors.lastname: Chicote
authors.forename: Oriol
authors.initials: O
authors.lastname: Arqués
authors.forename: Stefania
authors.initials: S
authors.lastname: Landolfi
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Fernández
authors.forename: José Raúl
authors.initials: JR
authors.lastname: Herance
authors.forename: Juan D
authors.initials: JD
authors.lastname: Gispert
authors.forename: Leire
authors.initials: L
authors.lastname: Mendizabal
authors.forename: Susana
authors.initials: S
authors.lastname: Aguilar
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón y Cajal
authors.forename: Simó
authors.initials: S
authors.lastname: Schwartz
authors.forename: Ana
authors.initials: A
authors.lastname: Vivancos
authors.forename: Eloy
authors.initials: E
authors.lastname: Espín
authors.forename: Santiago
authors.initials: S
authors.lastname: Rojas
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.forename: Héctor G
authors.initials: HG
authors.lastname: Palmer
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry; D002747:Chlorpropamide / Q000031:analogs & derivatives / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology*; D004318:Doxycycline / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000502:physiology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000032:analysis / Q000502:physiology*; D000096926:Benzenesulfonamides
chemical_list: D002747:Chlorpropamide; D004318:Doxycycline; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013629:Tamoxifen; D051176:beta Catenin; C111224:API 2; D000096926:Benzenesulfonamides; C495270:CTNNB1 protein, human; C499517:FOXO3 protein, human; C016601:afimoxifene