Regulation of lung cancer cell growth and invasiveness by beta-TRCP

Abstract

Beta-transducin-repeat-containing protein (beta-TRCP) serves as a substrate-recognition subunit of Skp1/Cullin/F-box (SCF)(beta-TRCP) E3 ligases, involved in regulation of several important signaling molecules. SCF(beta-TRCP) E3 ligases play a critical role in cell mitosis as well as in various signaling pathways. Here, we provide evidence to support that beta-TRCP negatively regulates cell growth and motility of lung cancer cells. With specific antibodies, we detect loss of beta-TRCP1 protein in several lung cancer cell lines. One cell line contains an inactivated mutation of the beta-TRCP1 gene. Loss of beta-TRCP1 protein is also found in subsets of lung cancer specimens. We observe that retrovirus-mediated stable expression of beta-TRCP1 in beta-TRCP1 negative cells inhibits cell growth in soft-agar and tumor formation in nude mice. Furthermore, expression of beta-TRCP1 alters cell motility, as indicated by morphological changes and a reduced level of active matrix metalloproteinase (MMP)11. Conversely, inactivation of beta-TRCP1 by specific siRNA accelerates cell invasion. Of the 10 known substrates of SCF(beta-TRCP) E3 ligases, the protein level of cell division cycle 25 (CDC25)A is clearly affected in these lung cancer cells. Cells treated with CDC25A inhibitors become less invasive. Thus, loss of beta-TRCP1 may promote both growth and cell motility of lung cancer cells, possibly through regulation of CDC25A and the MMP11 level.