Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells.
Lung cancer is the leading cause of cancer death. Lung cancers produce a variety of mitogenic growth factors that stimulate tumor cell proliferation and migration. The cell surface protease, dipeptidyl peptidase IV (DPPIV), is involved in diverse biologic functions, including peptide-mediated cellular growth and differentiation. DPPIV is expressed in various normal tissues, including lung tissue, and its expression is lost in many types of human cancers. DPPIV expression and its enzymatic activity are detected in normal bronchial and alveolar epithelium but different histologic subtypes of lung carcinomas lose DPPIV expression. To investigate the role of DPPIV in lung carcinoma, we examined the expression of DPPIV at both mRNA and protein levels in non small cell lung cancer (NSCLC) cell lines and normal human bronchial epithelial cells. DPPIV expression was detectable in normal lung epithelial cells, but was absent or markedly reduced in all NSCLC cell lines at both mRNA and protein levels. Restoration of DPPIV expression in NSCLC cells resulted in profound morphologic changes, inhibition of cell proliferation, anchorage-independent growth, in vitro cell migration and tumorigenicity in nude mice. DPPIV reexpression also correlated with increased p21 expression, leading to induction of apoptosis and cell cycle arrest in G1 stage. These effects were accompanied by increased expression of cell surface proteins, fibroblast-activating protein (Fapalpha) and CD44 that are associated with suppression of tumor growth and metastasis. Thus, DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells.
Wesley
Umadevi V
UV
Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA. uwesley@zoo.uvm.edu
Tiwari
Shakuntala
S
Houghton
Alan N
AN
D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D010450:Endopeptidases; D018093:Gelatinases; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099167:Fibroblast Activation Protein Alpha
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018819:Dipeptidyl Peptidase 4; D010450:Endopeptidases; D018093:Gelatinases; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D012333:RNA, Messenger; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse