Suppression of tumor metastasis by a RECK-activating small molecule

• Published in: Scientific reports Vol. 12; no. 1; p. 2319
• Main Authors: Yoshida, Yoko, Yuki, Kanako, Dan, Shingo, Yamazaki, Kanami, Noda, Makoto
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154; 631/67; 631/80; Angiogenesis; Animal models; Animals; Cell Line, Tumor; Disease Models, Animal; Drug Screening Assays, Antitumor - methods; Genes, Reporter; Genomes; GPI-Linked Proteins - metabolism; Humanities and Social Sciences; Humans; Krueppel-like factor; Kruppel-Like Transcription Factors - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Metastases; Metastasis; Mice; Mice, Inbred BALB C; multidisciplinary; Myc protein; Neoplasm Metastasis - prevention & control; Promoter Regions, Genetic; Science; Science (multidisciplinary); Transcription Factors - metabolism; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-06288-3

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.