Recombinant viral protein promotes apoptosis and suppresses invasion of ovarian adenocarcinoma cells by targeting α5β1 integrin to down-regulate Akt and MMP-2.

Abstract

BACKGROUND AND PURPOSE:

As prognosis for patients with metastatic ovarian cancer is generally poor, advances in treatment are needed. Here, we studied the mechanism of action of a recombinant viral capsid protein (rVP1) and explored its effect against ovarian tumour growth and metastasis in vivo.

EXPERIMENTAL APPROACH:

The human ovarian cancer cell line SKOV3 and BALB/cAnN-Foxn1 female nude mice were used. Effects of rVP1 on the viability, invasive ability, matrix metalloproteinase (MMP)-2 activity and cancer cell proliferation and metastasis were determined by cell proliferation assay, Matrigel invasion assay, gelatin zymographic analysis, as well as bioluminescence imaging and immunohistological analysis in xenograft mouse models respectively. Levels of total and phosphorylated focal adhesion kinase (FAK), PKB/Akt, phosphatase and tensin homologue (PTEN) and glycogen synthase kinase-3β (GSK-3β) were detected by Western blotting.

KEY RESULTS:

rVP1 promoted apoptosis and decreased invasion of human ovarian cancer cells. This effect of rVP1 was accompanied by activation of PTEN and GSK-3β as well as down-regulation of FAK, Akt and MMP-2. Anti-integrin antibodies or overexpression of constitutively active Akt reversed the cellular effects of rVP1. Orthotopic and intraperitoneal xenograft mouse models demonstrated that rVP1 attenuated survival and metastasis of human ovarian cancer SKOV3 cell line in vivo through selective regulation of Akt and GSK-3β activity as shown by bioluminescence imaging of mice and immunohistochemical analysis.

CONCLUSION AND IMPLICATIONS:

These results indicate that negative regulation of Akt signalling and MMP-2 by rVP1 may have the potential to suppress ovarian tumour growth and metastasis in vivo.

• Authors: Jei-Ming Peng, Yee-Hsiung Chen, Shao-Wen Hung, Ching-Feng Chiu, Ming-Yi Ho, Yi-Jen Lee, Tsung-Ching Lai, Michael Hsiao, Chi-Ming Liang, Shu-Mei Liang
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 165 Issue 2 Pg. 479-93 (Jan 2012) ISSN: 1476-5381 [Electronic] England
• PMID: 21740408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Capsid Proteins
• Integrin alpha5beta1
• Recombinant Proteins
• Proto-Oncogene Proteins c-akt
• Caspase 3
• Matrix Metalloproteinase 2

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Animals
• Apoptosis (drug effects)
• Capsid Proteins (pharmacology, therapeutic use)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• DNA Fragmentation
• Female
• Humans
• Integrin alpha5beta1 (metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Recombinant Proteins (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays