Insulin-like growth factor binding protein-6 inhibits the growth of human bronchial epithelial cells and increases in abundance with all-trans-retinoic acid treatment.
Retinoids are potent inhibitors of human bronchial epithelial (HBE) cell growth. Retinoids initiate signaling through activation of nuclear receptors, but the signal transduction pathways that mediate growth inhibition have not been defined. In this study, we investigated the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-6 as a potential mediator of retinoid actions. IGFBP-6 is a secreted glycoprotein that inhibits the bioavailability of IGFs, which are potent mitogens of HBE cells. IGFBP-6 was detected by immunohistochemical staining in the basal epithelial layer of human bronchial organ cultures, and all-trans-retinoic acid (t-RA) treatment increased the intensity of IGFBP-6 immunostaining. In primary cultures of HBE cells treated with t-RA, IGFBP-6 messenger RNA and protein levels increased within 6 and 24 h, respectively, and IGFBP-6 was detected in the conditioned media at 48 h. The effect of IGFBP-6 on HBE cell growth was investigated with a recombinant adenoviral vector, Ad5CMV-BP6, which expresses IGFBP-6 under the control of a cytomegalovirus promoter. IGFBP-6 overexpression induced a proliferative arrest of HBE cells with no evidence of apoptosis. These findings provide the first evidence that IGFBP-6 is expressed in the bronchial epithelium and that IGFBP-6 may contribute to the biologic effects of retinoids on HBE cells.
Sueoka
N
N
Department of Thoracic/Head and Neck Medical Oncology, Thoracic and Cardiovascular Surgery, and Molecular Oncology, University of Texas-M. D. Anderson Cancer Center, Houston, Texas, USA.
Lee
H Y
HY
Walsh
G L
GL
Fang
B
B
Ji
L
L
Roth
J A
JA
LaPushin
R
R
Hong
W K
WK
Cohen
P
P
Kurie
J M
JM
D000256:Adenoviridae / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D001980:Bronchi / Q000166:cytology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015870:Gene Expression / Q000502:physiology; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics* / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D020545:Respiratory Mucosa / Q000166:cytology*; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D018976:Insulin-Like Growth Factor Binding Protein 6; D008164:Luminescent Proteins; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D014212:Tretinoin