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A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing

Ryuya Murai1, Yoko Yoshida1, Teruyuki Muraguchi1

  • 1Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.

Oncotarget
|February 10, 2011
PubMed

Insights

The RECK protein, a cancer suppressor, can be reactivated by certain compounds. Disulfiram, an identified compound, significantly reduced lung metastasis in preclinical cancer models.

Area of Science:

  • Oncology
  • Molecular Biology

Background:

  • RECK (Reversion-Inducing Cysteine-Rich Protein-rich protein) is a membrane-anchored metalloproteinase regulator frequently downregulated in cancers.
  • Low RECK levels in tumors correlate with poor prognosis, while its forced expression inhibits cancer progression in models.
  • RECK is a potential biomarker for benignancy and a therapeutic target in cancer treatment.

Purpose of the Study:

  • To develop and validate a screening system for identifying compounds that can restore RECK expression in cancer cells.
  • To evaluate the therapeutic potential of RECK-inducing compounds in preclinical cancer models.

Main Methods:

  • Established a dual-transgene cell line with a RECK promoter-SEAP reporter and a Tet-off regulated HRAS(12V) oncogene.
  • Screened 880 bioactive compounds for RECK promoter activation in both transformed and untransformed cells.
  • Validated selected compounds for their ability to upregulate endogenous RECK protein and suppress metastasis in vivo.

Main Results:

  • Identified 34 compounds activating the RECK promoter, including 10 known anticancer drugs.
  • Four compounds demonstrated upregulation of endogenous RECK protein in human cancer cell lines.
  • Disulfiram, a top-ranked compound, significantly suppressed spontaneous lung metastasis of fibrosarcoma cells in mice.

Conclusions:

  • The developed cell line is effective for screening RECK-inducing compounds.
  • Disulfiram shows significant preclinical efficacy in suppressing cancer metastasis.
  • This screening approach holds promise for discovering novel cancer therapeutics targeting RECK.

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