Arkadia regulates tumor metastasis by modulation of the TGF-β pathway

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Arkadia regulates tumor metastasis by modulation of the TGF-β pathway. / Briones-Orta, Marco A; Levy, Laurence; Madsen, Chris D; Das, Debipriya; Erker, Yigit; Sahai, Erik; Hill, Caroline S.

I: Cancer Research, Vol. 73, Nr. 6, 15.03.2013, s. 1800-10.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Briones-Orta, MA, Levy, L, Madsen, CD, Das, D, Erker, Y, Sahai, E & Hill, CS 2013, 'Arkadia regulates tumor metastasis by modulation of the TGF-β pathway', Cancer Research, vol. 73, nr. 6, s. 1800-10. https://doi.org/10.1158/0008-5472.CAN-12-1916

APA

Briones-Orta, M. A., Levy, L., Madsen, C. D., Das, D., Erker, Y., Sahai, E., & Hill, C. S. (2013). Arkadia regulates tumor metastasis by modulation of the TGF-β pathway. Cancer Research, 73(6), 1800-10. https://doi.org/10.1158/0008-5472.CAN-12-1916

CBE

MLA

Vancouver

Author

Briones-Orta, Marco A ; Levy, Laurence ; Madsen, Chris D ; Das, Debipriya ; Erker, Yigit ; Sahai, Erik ; Hill, Caroline S. / Arkadia regulates tumor metastasis by modulation of the TGF-β pathway. I: Cancer Research. 2013 ; Vol. 73, Nr. 6. s. 1800-10.

RIS

TY - JOUR

T1 - Arkadia regulates tumor metastasis by modulation of the TGF-β pathway

AU - Briones-Orta, Marco A

AU - Levy, Laurence

AU - Madsen, Chris D

AU - Das, Debipriya

AU - Erker, Yigit

AU - Sahai, Erik

AU - Hill, Caroline S

PY - 2013/3/15

Y1 - 2013/3/15

N2 - TGF-β can act as a tumor suppressor at early stages of cancer progression and as a tumor promoter at later stages. The E3 ubiquitin ligase Arkadia (RNF111) is a critical component of the TGF-β signaling pathway, being required for a subset of responses, those mediated by Smad3-Smad4 complexes. It acts by mediating ligand-induced degradation of Ski and SnoN (SKIL), which are 2 potent transcriptional repressors. Here, we investigate the role of Arkadia in cancer using model systems to address both potential tumor-suppressive and tumor-promoting roles. Stable reexpression of Arkadia in lung carcinoma NCI-H460 cells, which we show contain a hemizygous nonsense mutation in the Arkadia/RNF111 gene, efficiently restored TGF-β-induced Smad3-dependent transcription, and substantially decreased the ability of these cells to grow in soft agar in vitro. However, it had no effect on tumor growth in vivo in mouse models. Moreover, loss of Arkadia in cancer cell lines and human tumors is rare, arguing against a prominent tumor-suppressive role. In contrast, we have uncovered a potent tumor-promoting function for Arkadia. Using 3 different cancer cell lines whose tumorigenic properties are driven by TGF-β signaling, we show that loss of Arkadia function, either by overexpression of dominant negative Arkadia or by siRNA-induced knockdown, substantially inhibited lung colonization in tail vein injection experiments in immunodeficient mice. Our findings indicate that Arkadia is not critical for regulating tumor growth per se, but is required for the early stages of cancer cell colonization at the sites of metastasis.

AB - TGF-β can act as a tumor suppressor at early stages of cancer progression and as a tumor promoter at later stages. The E3 ubiquitin ligase Arkadia (RNF111) is a critical component of the TGF-β signaling pathway, being required for a subset of responses, those mediated by Smad3-Smad4 complexes. It acts by mediating ligand-induced degradation of Ski and SnoN (SKIL), which are 2 potent transcriptional repressors. Here, we investigate the role of Arkadia in cancer using model systems to address both potential tumor-suppressive and tumor-promoting roles. Stable reexpression of Arkadia in lung carcinoma NCI-H460 cells, which we show contain a hemizygous nonsense mutation in the Arkadia/RNF111 gene, efficiently restored TGF-β-induced Smad3-dependent transcription, and substantially decreased the ability of these cells to grow in soft agar in vitro. However, it had no effect on tumor growth in vivo in mouse models. Moreover, loss of Arkadia in cancer cell lines and human tumors is rare, arguing against a prominent tumor-suppressive role. In contrast, we have uncovered a potent tumor-promoting function for Arkadia. Using 3 different cancer cell lines whose tumorigenic properties are driven by TGF-β signaling, we show that loss of Arkadia function, either by overexpression of dominant negative Arkadia or by siRNA-induced knockdown, substantially inhibited lung colonization in tail vein injection experiments in immunodeficient mice. Our findings indicate that Arkadia is not critical for regulating tumor growth per se, but is required for the early stages of cancer cell colonization at the sites of metastasis.

KW - Animals

KW - Biocatalysis

KW - Blotting, Western

KW - Cell Line, Tumor

KW - Humans

KW - Mice

KW - Mutation

KW - Neoplasm Metastasis

KW - Nuclear Proteins

KW - Smad3 Protein

KW - Transcription, Genetic

KW - Transforming Growth Factor beta

KW - Ubiquitin-Protein Ligases

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1158/0008-5472.CAN-12-1916

DO - 10.1158/0008-5472.CAN-12-1916

M3 - Article

VL - 73

SP - 1800

EP - 1810

JO - Cancer research. Supplement

T2 - Cancer research. Supplement

JF - Cancer research. Supplement

SN - 1538-7445

IS - 6

ER -