title: Protein secretion is required for pregnancy-associated plasma protein-A to promote lung cancer growth in vivo.
abstract: Pregnancy-associated plasma protein-A (PAPPA) has been reported to regulate the activity of insulin-like growth factor (IGF) signal pathway through proteolytic degradation of IGF binding proteins (IGFBPs) thereby increasing the local concentration of free IGFs available to receptors. In this study we found that PAPPA is secreted from two out of seven lung cancer cell lines examined. None of immortalized normal bronchial epithelial cells (HBE) tested secrets PAPPA. There is no correlation between expression level and secretion of PAPPA in these cells. A cell line over-expressing PAPPA accompanied with secretion shows no notable changes in proliferation under cell culture conditions in vitro, but displays significantly augmentation of tumor growth in vivo in a xenograft model. In contrast, a cell line over-expressing PAPPA without secretion exhibits reduction of tumor growth both in vitro and in vivo. Down-regulation of PAPPA expression and secretion by RNAi knockdown decreases tumor growth after implanted in vivo. The tumor promoting activity of PAPPA appears to be mediated mainly through augmentation of the IGF signaling pathway as indicated by notable increases in downstream Akt kinase phosphorylation in tumor samples. Our results indicate that PAPPA secretion may play an important role in lung cancer growth and progression.
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, Maryland, United States of America.
authors.forename: Hong
authors.initials: H
authors.lastname: Pan
authors.forename: Sayaka
authors.initials: S
authors.lastname: Hanada
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Mao
authors.forename: Mark Zhi-Qing
authors.initials: MZ
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D047368:Tumor Burden
chemical_list: D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D011266:Pregnancy-Associated Plasma Protein-A