Osteopontin and MMP9: Associations with VEGF Expression/Secretion and Angiogenesis in PC3 Prostate Cancer Cells

Aditi Gupta,Meenakshi Chellaiah,Cindy Zhou

doi:10.3390/cancers5020617

Aditi Gupta, Meenakshi Chellaiah + Show 1 more

Open Access

https://doi.org/10.3390/cancers5020617

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Journal: Cancers	Publication Date: May 27, 2013
Citations: 103	License type: CC BY 4.0

Affiliation: University of Maryland, Baltimore

Abstract

Osteopontin and MMP9 are implicated in angiogenesis and cancer progression. The objective of this study is to gain insight into the molecular mechanisms underlying angiogenesis, and to elucidate the role of osteopontin in this process. We report here that osteopontin/αvβ3 signaling pathway which involves ERK1/2 phosphorylation regulates the expression of VEGF. An inhibitor to MEK or curcumin significantly suppressed the phosphorylation of ERK1/2 and expression of VEGF. MMP9 knockdown reduces the secretion but not the expression of VEGF. Moreover, MMP9 knockdown increases the release of angiostatin, a key protein that suppresses angiogenesis. Conditioned media from PC3 cells treated with curcumin or MEK inhibitor inhibited tube formation in vitro in human microvascular endothelial cells. Similar inhibitory effect on tube formation was found with conditioned media collected from PC3 cells expressing mutant-osteopontin at integrin-binding site and knockdown of osteopontin or MMP9. We conclude that MMP9 activation is associated with angiogenesis via regulation of secretion of VEGF and angiostatin in PC3 cells. Curcumin is thus a potential drug for cancer treatment because it demonstrated anti-angiogenic and anti-invasive properties.

Highlights

Prostate cancer is the second leading cancer that causes death in men and it is the most commonly diagnosed cancer in the U.S It is a disease of extensive metastasis, with secondary lesions in the lymph node, brain, bones, and sometimes in visceral organs such as liver and lungs
Vascular endothelial growth factor (VEGF)-165b is implicated as anti-angiogenic factor [9]
To determine the contribution of OPN/αvβ3 signaling in the expression of VEGF and angiogenesis, we have used PC3/OPN (RGA) which demonstrated a decrease in integrin signaling [18]

Summary

Introduction

Prostate cancer is the second leading cancer that causes death in men and it is the most commonly diagnosed cancer in the U.S It is a disease of extensive metastasis, with secondary lesions in the lymph node, brain, bones, and sometimes in visceral organs such as liver and lungs. Metastasis of malignant tumor cells is dependent on the formation of new blood vessels from existing ones, a process which is known as angiogenesis [1]. It is one of the fundamental processes required for solid tumor growth, survival and metastasis. Vascular endothelial growth factor (VEGF) is known to be one of the most potent angiogenic factor due to its specificity to endothelial cells [2]. VEGF, a 34–42 kDa glycoprotein recognizes two major tyrosine kinase receptors (VEGF-R1 and -R2)

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