Suppression of cell proliferation and signaling transduction by connective tissue growth factor in non-small cell lung cancer cells.
Connective tissue growth factor (CTGF) is a secreted protein that belongs to CCN family. The proteins in this family are implicated in various biological processes, such as angiogenesis, adhesion, migration, and apoptosis. In this study, we explored the roles of CTGF in lung tumorigenesis. The expression levels of CTGF in 58 lung cancer samples were reduced by >2 fold in 57% of the samples compared with matched normal samples using real-time reverse transcription-PCR. These results were confirmed by immunohistochemical staining for CTGF in normal lung epithelia and lung cancer. Cellular proliferation was inhibited in non-small cell lung cancer (NSCLC) cell lines NCI-H460, NCI-H520, NCI-H1299, and SK-MES-1 by CTGF overexpression. Partially purified CTGF suppressed lung cancer cell growth. The growth inhibition caused by CTGF overexpression was associated with growth arrest at G(0)-G(1) and prominent induction of p53 and ADP ribosylation factor. Most interestingly, overexpression of CTGF suppressed insulin-like growth factor-I-dependent Akt phosphorylation and epidermal growth factor-dependent extracellular signal-regulated kinase 1/2 phosphorylation. In summary, NSCLC cells expressed decreased levels of CTGF compared with normal lung cells; this lower expression has an effect on lung cancer cell proliferation and its cellular response to growth factors. Our data suggest that CTGF may behave as a secreted tumor suppressor protein in the normal lung, and its expression is suppressed in many NSCLCs.
Chien
Wenwen
W
Division of Hematology/Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, D5022, Los Angeles, CA 90048, USA.
Yin
Dong
D
Gui
Dorina
D
Mori
Akio
A
Frank
Jonathan Mordechai
JM
Said
Jonathan
J
Kusuanco
Donato
D
Marchevsky
Alberto
A
McKenna
Robert
R
Koeffler
H Phillip
HP
D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism; D015870:Gene Expression; D006131:Growth Inhibitors / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism* / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
C526317:CCN2 protein, human; D017077:Culture Media, Conditioned; D006131:Growth Inhibitors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055513:Connective Tissue Growth Factor; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D051058:Oncogene Protein v-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3