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

• Published in: Molecular carcinogenesis Vol. 42; no. 1; pp. 18 - 28
• Main Authors: He, Nonggao, Li, Chengxin, Zhang, Xiaoli, Sheng, Tao, Chi, Sumin, Chen, Kai, Wang, Qian, Vertrees, Roger, Logrono, Roberto, Xie, Jingwu
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.01.2005
• Subjects: beta-Transducin Repeat-Containing Proteins - metabolism; cdc25 Phosphatases - metabolism; CDC25A; cell invasion; Humans; lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Neoplasm Invasiveness - pathology; SCF; ubiquitination; β-TRCP
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.20063

Beta‐transducin‐repeat‐containing protein (β‐TRCP) serves as a substrate‐recognition subunit of Skp1/Cullin/F‐box (SCF)β‐TRCP E3 ligases, involved in regulation of several important signaling molecules. SCFβ‐TRCP E3 ligases play a critical role in cell mitosis as well as in various signaling pathways. Here, we provide evidence to support that β‐TRCP negatively regulates cell growth and motility of lung cancer cells. With specific antibodies, we detect loss of β‐TRCP1 protein in several lung cancer cell lines. One cell line contains an inactivated mutation of the β‐TRCP1 gene. Loss of β‐TRCP1 protein is also found in subsets of lung cancer specimens. We observe that retrovirus‐mediated stable expression of β‐TRCP1 in β‐TRCP1 negative cells inhibits cell growth in soft‐agar and tumor formation in nude mice. Furthermore, expression of β‐TRCP1 alters cell motility, as indicated by morphological changes and a reduced level of active matrix metalloproteinase (MMP)11. Conversely, inactivation of β‐TRCP1 by specific siRNA accelerates cell invasion. Of the 10 known substrates of SCFβ‐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 β‐TRCP1 may promote both growth and cell motility of lung cancer cells, possibly through regulation of CDC25A and the MMP11 level. © 2004 Wiley‐Liss, Inc.