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Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXR-gamma activation

ABSTRACT: Tumor metastasis and lack of NKG2D ligand (NKG2DL) expression are associated with poor prognosis in patients with colon cancer. Here we found that spironolactone (SPIR), an FDA-approved diuretic drug with a long-term safety profile, can upregulate NKG2DL expression in multiple colon cancer cell lines by activating the ATM-Chk2-mediated checkpoint pathway, which in turn enhances tumor elimination by natural killer cells. SPIR can also upregulate the expression of metastasis-suppressor genes TIMP2 and TIMP3, thereby reducing tumor cell invasiveness. Although SPIR is an aldosterone antagonist, its anti-tumor effects are independent of the mineralocorticoid receptor pathway. Instead, by screening the human nuclear hormone receptor siRNA library, we identify retinoid X receptor gamma (RXR gamma) as being indispensable for the anti-tumor functions of SPIR. Collectively, our results strongly support the use of SPIR or other RXR gamma-agonists with minimal side effects for colon cancer prevention and therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE50010 | GEO | 2013/10/22

SECONDARY ACCESSION(S): PRJNA215809

REPOSITORIES: GEO

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Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXR-gamma activation

Project description:Tumor metastasis and lack of NKG2D ligand (NKG2DL) expression are associated with poor prognosis in patients with colon cancer. Here we found that spironolactone (SPIR), an FDA-approved diuretic drug with a long-term safety profile, can upregulate NKG2DL expression in multiple colon cancer cell lines by activating the ATM-Chk2-mediated checkpoint pathway, which in turn enhances tumor elimination by natural killer cells. SPIR can also upregulate the expression of metastasis-suppressor genes TIMP2 and TIMP3, thereby reducing tumor cell invasiveness. Although SPIR is an aldosterone antagonist, its anti-tumor effects are independent of the mineralocorticoid receptor pathway. Instead, by screening the human nuclear hormone receptor siRNA library, we identify retinoid X receptor gamma (RXR gamma) as being indispensable for the anti-tumor functions of SPIR. Collectively, our results strongly support the use of SPIR or other RXR gamma-agonists with minimal side effects for colon cancer prevention and therapy. Two replicates of two cell types with and without drug

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Expression data from human primary skeletal muscle myotubes treated with aldosterone, spironolactone, or vehicle.

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Spironolactone effect on renal RNA expression in 36 wk old NZB/W F1 female mice

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