Loss of p53 and MCT-1 Overexpression Synergistically Promote Chromosome Instability and Tumorigenicity

• Published in: Molecular cancer research 2009-04, Vol.7 (4), p.536-548
• Main Authors: Kasiappan, Ravi, Shih, Hung-Ju, Chu, Kang-Lin, Chen, Wei-Ti, Liu, Hui-Ping, Huang, Shiu-Feng, Choy, Chik On, Shu, Chung-Li, Din, Richard, Chu, Jan-Show, Hsu, Hsin-Ling
• Format: Article
• Language: English
• Subjects: Aneuploidy; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Adhesion - physiology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Movement - physiology; Cell Proliferation; Chromosomal Instability; chromosome instability; Cytogenetic Analysis; Drug Synergism; Etoposide - pharmacology; Female; Flow Cytometry; Humans; Immunoblotting; Immunoenzyme Techniques; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; MCT-1 oncogene; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Mutagens - pharmacology; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; p53; Proto-Oncogene Proteins c-raf - genetics; Proto-Oncogene Proteins c-raf - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Translocation, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-08-0422

MCT-1 oncoprotein accelerates p53 degradation by means of the ubiquitin-dependent proteolysis. Our present data show that induction of MCT-1 increases chromosomal translocations and deregulated G 2 -M checkpoint in response to chemotherapeutic genotoxin. Remarkably, increases in chromosome copy number, multinucleation, and cytokinesis failure are also promoted while MCT-1 is induced in p53-deficient cells. In such a circumstance, the Ras–mitogen-activated protein kinase/extracellular signal-regulated kinase kinase–mitogen-activated protein kinase signaling activity and the expression of metastatic molecules are amplified. Given a p53-silencing background, MCT-1 malignantly transforms normal breast epithelial cells that are satisfactory for stimulating cell migration/adhesion and tumorigenesis. Detailed analyses of MCT-1 oncogenicity in H1299 p53-null lung cancer cells have shown that ectopically expressed MCT-1 advances xenograft tumorigenicity and angiogenesis, which cannot be completely suppressed by induction of p53. MCT-1 counteracts mutually with p53 at transcriptional levels. Clinical validations confirm that MCT-1 mRNA levels are differentially enriched in comparison between human lung cancer and nontumorigenic tissues. The levels of p53 mRNA are comparatively reduced in a subset of cancer specimens, which highly present MCT-1 mRNA. Our results indicate that synergistic promotions of chromosomal imbalances and oncogenic potency as a result of MCT-1 expression and p53 loss play important roles in tumor development. (Mol Cancer Res 2009;7(4):536–48)