Suppression of tumor metastasis by a RECK-activating small molecule
Yoko Yoshida1,2, Kanako Yuki3, Shingo Dan4
1Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, 606-8501, Japan. yoko.yoshida@jfcr.or.jp.
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.
Insights
A novel compound, DSK638, effectively suppresses cancer metastasis by inducing RECK (Reduced Expression in Carcinomas of the Kidney) and MXI1. This approach offers a promising strategy for developing new anti-metastasis drugs.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- RECK (Reduced Expression in Carcinomas of the Kidney) is a tumor suppressor frequently downregulated in various cancers, correlating with poor prognosis.
- Reduced RECK expression is linked to increased tumor angiogenesis, invasion, and metastasis.
- RECK mutations are rare, indicating potential therapeutic value in reactivating its expression.
Purpose of the Study:
- To identify and evaluate novel agents that can induce RECK expression for cancer therapy.
- To investigate the mechanism of RECK induction and its effect on metastasis.
- To assess the therapeutic potential of RECK-inducing compounds in preclinical models.
Main Methods:
- Utilized a reporter assay system to screen for RECK inducers.
- Employed mouse xenograft models to evaluate the anti-metastatic effects of candidate compounds.
- Investigated the molecular mechanisms of RECK induction, including transcription factor involvement (SP1, KLF2).
- Assessed the role of MXI1 (a MYC antagonist) in the compound's efficacy.
Main Results:
- Identified DSK638 as a potent inducer of RECK expression.
- DSK638 significantly inhibited spontaneous lung metastasis in a mouse xenograft model.
- RECK induction by DSK638 involves SP1 sites and potentially KLF2.
- DSK638 also upregulated MXI1, and its anti-metastatic effect was dependent on both RECK and MXI1.
Conclusions:
- DSK638 is a promising therapeutic agent for inhibiting cancer metastasis.
- Reactivating RECK expression is a viable strategy for cancer treatment.
- The combination of RECK induction and MXI1 upregulation contributes to DSK638's efficacy.
- The developed screening approach is effective for identifying metastasis-suppressing drugs.
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