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Diverse mechanisms of Wnt activation and effects of pathway inhibition on proliferation of human gastric carcinoma cells

Oncogene volume 30, pages 956–966 (2011)Cite this article

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Abstract

Human gastric carcinomas are among the most treatment-refractory epithelial malignancies. Increased understanding of the underlying molecular aberrations in such tumors could provide insights leading to improved therapeutic approaches. In this study, we characterized diverse genetic aberrations leading to constitutive Wnt signaling activation in a series of human gastric carcinoma cell lines. Downregulation of TCF signaling by stable transduction of dominant negative TCF4 (DNTCF4) resulted in inhibition of proliferation in Wnt-activated AGS tumor cells. c-Myc downregulation and the associated upregulation of its repression target, p21 observed in these tumor cells, as well as the profound growth inhibition induced by c-Myc small hairpin RNA (shRNA) implied their c-Myc addiction. In striking contrast, Wnt-activated MKN-28 and MKN-74 tumor cells appeared refractory to DNTCF4 inhibition of proliferation despite comparably decreased c-Myc expression levels. The resistance of these same tumor cells to growth inhibition by c-Myc shRNA established that their refractoriness to DNTCF was because of their independence from c-Myc for proliferation. There was no correlation between this resistance phenotype and the presence or absence of constitutive mitogen-activated protein kinase (MAPK) and/or AKT pathway activation, commonly observed in gastrointestinal tumors. However, in both DNTCF-sensitive and -resistant tumor cells with MAPK and/or AKT pathway activation, the ability of small molecule antagonists directed against either pathway to inhibit tumor cell growth was enhanced by Wnt pathway inhibition. These findings support the concept that although certain Wnt-activated tumors may escape c-Myc dependence for proliferation, disruption of other oncogenic pathways can unmask cooperative antiproliferative effects for Wnt pathway downregulation.

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Abbreviations

(MAPK):

Ras/Raf/Erk

(PI3K/AKT):

phosphatidylinositol 3-kinase/AKT

(CRC):

colorectal cancer

(FACS):

fluorescence activated cell sorting

TCF:

T-cell factors

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Acknowledgements

We are grateful to Dr Yoshio Yamaoka (Baylor College of Medicine, Houston, TX, USA) for MKN-7 and MKN-28 cells; Dr Gary Schwartz (Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA) for MKN-74 cells and Dr Reuben Lotan (MD Anderson Cancer Center, Houston, TX, USA) for KATO-II cells. SV is a recipient of a post-doctoral fellowship award from the American Urological Association. Grant support: This work was supported by grant number 5R01CA071672 from the National Cancer Institute.

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  1. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, USA

    S Asciutti, G Akiri, L Grumolato, S Vijayakumar & S A Aaronson

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  1. S Asciutti
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  2. G Akiri
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Correspondence to S A Aaronson.

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Asciutti, S., Akiri, G., Grumolato, L. et al. Diverse mechanisms of Wnt activation and effects of pathway inhibition on proliferation of human gastric carcinoma cells. Oncogene 30, 956–966 (2011). https://doi.org/10.1038/onc.2010.475

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