Genetic downregulation of pregnancy-associated plasma protein-A (PAPP-A) by bikunin reduces IGF-I-dependent Akt and ERK1/2 activation and subsequently reduces ovarian cancer cell growth, invasion and metastasis
✍ Scribed by Yoshiko Tanaka; Hiroshi Kobayashi; Mika Suzuki; Yasuyuki Hirashima; Naohiro Kanayama; Toshihiko Terao
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- French
- Weight
- 559 KB
- Volume
- 109
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Abstract
A Kunitz‐type protease inhibitor, bikunin, downregulates expression of uPA and its receptor uPAR at the mRNA and protein levels in several types of tumor cells. Our recent work showed that, using a cDNA microarray analysis, pregnancy‐associated plasma protein‐A (PAPP‐A) is a candidate bikunin target gene. To clarify how reduced levels of PAPP‐A may confer repressed invasiveness, we transfected human ovarian cancer cell line HRA with antisense (AS)‐PAPP‐A cDNA and compared the properties of the transfected cells to those of parental HRA cells. Here, we show that regulation of uPA mRNA and protein by IGF‐I depends on the PI3K and MAPK signaling pathways and phosphorylation of Akt and ERK1/2 is required for IGF‐I‐mediated cell invasion; that IGFBP‐4 protease in HRA cells is identified as PAPP‐A; that reduced PAPP‐A expression is associated with the upregulation of IGFBP‐4 expression; that higher intact IGFBP‐4 levels were associated with low invasive potential and growth rate in AS‐PAPP‐A cells in response to IGF‐I; that IGF‐I stimulates Akt and ERK1/2 activation of both the control and antisense cells, but the relative potency and efficacy of IGF‐I were lower in the antisense cells compared to the control; and that genetic downregulation of PAPP‐A reduces the proliferation, invasion and metastasis of HRA cells. In conclusion, our data identify a novel role for PAPP‐A as a bikunin target gene. IGF‐I‐induced IGFBP‐4 proteolysis by PAPP‐A may enhance cell growth and invasion through IGF‐I‐dependent Akt and ERK1/2 activation and subsequently upregulation of uPA. © 2004 Wiley‐Liss, Inc.