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Targeting Wnt/tenascin C-mediated cross talk between pancreatic cancer cells and stellate cells via activation of the metastasis suppressor NDRG1.
Geleta, Bekesho; Tout, Faten S; Lim, Syer Choon; Sahni, Sumit; Jansson, Patric J; Apte, Minoti V; Richardson, Des R; Kovacevic, Zaklina.
Afiliação
  • Geleta B; Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia.
  • Tout FS; Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Department of Medical Laboratory S
  • Lim SC; Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia.
  • Sahni S; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
  • Jansson PJ; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia; Cancer Drug Resistanc
  • Apte MV; Pancreatic Research Group, South Western Sydney Clinical School, UNSW Sydney, Sydney, New South Wales, Australia; Pancreatic Research Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia.
  • Richardson DR; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, Australia; Department of Patho
  • Kovacevic Z; Cancer Metastasis and Tumor Microenvironment Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia; Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia. Electronic address: zaklina.kovace
J Biol Chem ; 298(3): 101608, 2022 03.
Article em En | MEDLINE | ID: mdl-35065073
A major barrier to successful pancreatic cancer (PC) treatment is the surrounding stroma, which secretes growth factors/cytokines that promote PC progression. Wnt and tenascin C (TnC) are key ligands secreted by stromal pancreatic stellate cells (PSCs) that then act on PC cells in a paracrine manner to activate the oncogenic ß-catenin and YAP/TAZ signaling pathways. Therefore, therapies targeting oncogenic Wnt/TnC cross talk between PC cells and PSCs constitute a promising new therapeutic approach for PC treatment. The metastasis suppressor N-myc downstream-regulated gene-1 (NDRG1) inhibits tumor progression and metastasis in numerous cancers, including PC. We demonstrate herein that targeting NDRG1 using the clinically trialed anticancer agent di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) inhibited Wnt/TnC-mediated interactions between PC cells and the surrounding PSCs. Mechanistically, NDRG1 and DpC markedly inhibit secretion of Wnt3a and TnC by PSCs, while also attenuating Wnt/ß-catenin and YAP/TAZ activation and downstream signaling in PC cells. This antioncogenic activity was mediated by direct inhibition of ß-catenin and YAP/TAZ nuclear localization and by increasing the Wnt inhibitor, DKK1. Expression of NDRG1 also inhibited transforming growth factor (TGF)-ß secretion by PC cells, a key mechanism by which PC cells activate PSCs. Using an in vivo orthotopic PC mouse model, we show DpC downregulated ß-catenin, TnC, and YAP/TAZ, while potently increasing NDRG1 expression in PC tumors. We conclude that NDRG1 and DpC inhibit Wnt/TnC-mediated interactions between PC cells and PSCs. These results further illuminate the antioncogenic mechanism of NDRG1 and the potential of targeting this metastasis suppressor to overcome the oncogenic effects of the PC-PSC interaction.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Comunicação Celular / Proteínas de Ciclo Celular / Tenascina / Peptídeos e Proteínas de Sinalização Intracelular / Beta Catenina / Células Estreladas do Pâncreas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Biol Chem Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Austrália
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Comunicação Celular / Proteínas de Ciclo Celular / Tenascina / Peptídeos e Proteínas de Sinalização Intracelular / Beta Catenina / Células Estreladas do Pâncreas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Biol Chem Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Austrália