Involvement of the SKP2-p27(KIP1) pathway in suppression of cancer cell proliferation by RECK.

The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in cancers; in some cases, a significant correlation between the level of residual RECK in resected tumors and patient survival has been noted. Furthermore, restoration of RECK expression in certain cancer-derived cell lines results in reduced tumorigenicity. Here we report that acute RECK expression in colon carcinoma cells results in cell cycle-arrest accompanied by downregulation of a ubiquitin ligase component, S-phase kinase-associated protein 2 (SKP2), and upregulation of its substrate, p27(KIP1). Our data indicate that RECK-induced growth suppression is at least partially dependent on p27, and that RECK and type I collagen share similar effects on the SKP2-p27 pathway. Importantly, in patients with lung, colorectal and bladder cancers, the RECK/SKP2 ratio is high in normal tissues and lower in the cancer tissues. These findings reveal a novel molecular pathway linking cell-cycle progression to RECK downregulation, extracellular matrix degradation and SKP2 upregulation, and suggest that treatment regimens that induce RECK expression could be promising cancer therapies.