Activation of Matrix Metalloproteinase-2 by Overexpression of Manganese Superoxide Dismutase in Human Breast Cancer MCF-7 Cells Involves Reactive Oxygen Species

Abstract

Cancer metastasis is a multistep process that includes invasion of cancer cells into blood vessels, traveling of these cells in the circulation system, and proliferation and eventual formation of a metastatic tumor at distal tissues. Among these steps, the first step of cancer cell invasion is a critical point for cancer metastasis. A current hypothesis proposes that remodeling of the extracellular matrix is a required process for cancer cell invasion (1, 2).The process of extracellular matrix remodeling happens in both normal physiological conditions and pathological diseases such as cancer invasion. Cancer invasion is a disordered and uncontrolled behavior that usually involves the interaction of tumor cells and their surrounding stromal cells, leading to the loss of matrix function and a compromised matrix boundary. Although several classes of proteases have been suggested in extracellular matrix remodeling, previous studies have demonstrated that the activation of zinc-dependent matrix metalloproteinases (MMPs) 1 was the primary response for the degradation of components of the extracellular matrix (3, 4).There are at least 15 members in the MMP family. MMP-2 (also called gelatinase A-type IV collagenase) and MMP-9 (geletinase B-type IV collagenase), two members of the MMP family, were postulated to play a critical role in tumor invasion. Lotta et al. have shown that the activities of MMP-2 and MMP-9 were higher in human breast cancer than the premalignant or normal breast tissue (1). In addition, in an experimental metastatic model, Stetler-Stevenson (5) has concluded that the protein level and activity of both enzymes were correlated with the metastatic potential of tumor cells.MMPs share similar mechanisms of activation and protease function. The regulation of MMP activation occurs at both mRNA and/or protein levels. For example, transforming growth factor-␤1 increases progelatinase mRNA levels in human fibroblasts (6). In addition, most MMPs are secreted as zymogens upon translation. Post-translational modification is required for MMP activation to acquire the proteolytic function.Previously, oxidation and oxidative stress have been implicated in the regulation of MMP activation. Increases in MMP-2 mRNA level and enzymatic activity were seen following xanthine/xanthine oxidase (X/XO) treatment (7) and ionizing radiation (8). It is well known that both the X/XO system and radiation produce reactive oxygen species (ROS) such as superoxide radicals and hydrogen peroxide. In fact, hydrogen perox-* This work was supported by NCI, National Institutes of Health (NIH), Grants P01 CA 66081 and CA84462, Public Health Service Grants AG 12350 and AG 14687, and NIDDK, NIH, Grant 51612. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.¶ To whom correspondence should be addressed: Free Radical and Radiation Biology, Dept. of Radiation Oncology,...

A new activating role for CO in cardiac mitochondrial biogenesis

“…CO also upregulates SOD2, which scavenges superoxide, augments mitochondrial H 2 O 2 release, and may modulate redox signaling (Zhang et al, 2002). In cardiomyocytes, mitochondrial CC-1 uptake in the presence of CO was blocked by mitochondrialtargeted catalase.…”

“…The CO to cytochrome a 3 stoichiometry was too low to compromise aerobic energy production to the point of damage, and indicated a high gain of mitochondrial biogenesis to mitochondrial oxidation-reduction state. For instance, the spectral data suggest that the CO:O 2 ratio adjusts electron transport in conjunction with the Q cycle to regulate superoxide production and the H 2 O 2 leak rate via SOD2 (Trumpower, 1990;Zhang et al, 2002) (Fig. 7).…”

MnSOD Promotes Tumor Invasion via Upregulation of FoxM1–MMP2 Axis and Related with Poor Survival and Relapse in Lung Adenocarcinomas

“…An early report on MCF-7 breast cancer cells indicated that MnSOD induced MMP2 expression by regulation of intracellular ROS (21). Another report showed that MMP2 transcription was directly upregulated by FoxM1 and that the invasion of glioma cells was enhanced by FoxM1-induced MMP2 expression (30).…”

“…Zhang and colleagues showed activation of MMP2 by MnSOD in human breast cancer MCF-7 cells via the regulation of intracellular reactive oxygen species (ROS; ref. 21). A study on immunodeficient mice showed that MnSOD promoted the metastastic potential of fibrosarcoma cells via increased levels of MMP1 mRNA (22).…”

Roles of Oxidative Stress in the Development and Progression of Breast Cancer

“…Glutathione peroxidase (GPX) and catalase (CAT) are enzymes that cause the inactivation of MMP-2 and decrease mass migration of breast cancer cells which are associated with MMPs through the reduction and elimination of hydrogen peroxide (Zhang et al, 2002).…”