Abstract
RECK encodes a membrane-anchored protease-regulator which is often downregulated in a wide variety of cancers, and reduced RECK expression often correlates with poorer prognoses. In mouse models, forced expression of RECK in tumor xenografts results in suppression of tumor angiogenesis, invasion, and metastasis. RECK mutations, however, are rare in cancer genomes, suggesting that agents that re-activate dormant RECK may be of clinical value. We found a potent RECK-inducer, DSK638, that inhibits spontaneous lung metastasis in our mouse xenograft model. Induction of RECK expression involves SP1 sites in its promoter and may be mediated by KLF2. DSK638 also upregulates MXI1, an endogenous MYC-antagonist, and inhibition of metastasis by DSK638 is dependent on both RECK and MXI1. This study demonstrates the utility of our approach (using a simple reporter assay followed by multiple phenotypic assays) and DSK638 itself (as a reference compound) in finding potential metastasis-suppressing drugs.
Highlights
RECK encodes a membrane-anchored protease-regulator which is often downregulated in a wide variety of cancers, and reduced RECK expression often correlates with poorer prognoses
RECK is downregulated in a wide variety of cancers, and reduced RECK expression often correlates with poorer p rognoses[12–14]
RECK mutations, are rare in cancer genomes, suggesting that RECK expression is transcriptionally and/ or epigenetically suppressed and agents that can re-activate dormant RECK in cancer cells may be of clinical value
Summary
RECK encodes a membrane-anchored protease-regulator which is often downregulated in a wide variety of cancers, and reduced RECK expression often correlates with poorer prognoses. In mouse models, forced expression of RECK in tumor xenografts results in suppression of tumor angiogenesis, invasion, and metastasis. In mouse xenograft models, forced expression of RECK in tumor cells results in suppression of tumor angiogenesis, invasion, and m etastasis[7], suggesting that RECK-downregulation plays a causal role in tumorigenesis. RECK mutations, are rare in cancer genomes, suggesting that RECK expression is transcriptionally and/ or epigenetically suppressed and agents that can re-activate dormant RECK in cancer cells may be of clinical value. We performed a high throughput screen using a RECK-promoter-reporter assay and found a potent RECK-inducer, DSK638, that inhibits metastasis in a mouse xenograft model. A series of transcriptome analyses were performed to gain insights into the molecular mechanisms of metastasis suppression by DSK638, and involvement of candidate genes was experimentally validated
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