The Regulatory Mechanism of Extracellular Hsp90α on Matrix Metalloproteinase-2 Processing and Tumor Angiogenesis

Abstract

Heat shock protein 90␣ (Hsp90␣) is a ubiquitously expressed molecular chaperone that is essential for eukaryotic homeostasis. Hsp90␣ can also be secreted extracellularly, where it has been shown to be involved in tumor metastasis. Extracellular Hsp90␣ interacts with and promotes the proteolytic activity of matrix metalloproteinase-2 (MMP-2). However, the regulatory mechanism of Hsp90␣ on MMP-2 activity is still unknown. Here we show that Hsp90␣ stabilizes MMP-2 and protects it from degradation in tumor cells. Further investigation reveals that this stabilization effect is isoform-specific, ATP-independent, and mediated by the interaction between the Hsp90␣ middle domain and the MMP-2 C-terminal hemopexin domain. Moreover, this mechanism also applies to endothelial cells that secrete more Hsp90␣ in their proliferating status. Furthermore, endothelial cell transmigration, Matrigel plug, and tumor angiogenesis assays demonstrate that extracellular Hsp90␣ promotes angiogenesis in an MMP-2-dependent manner. In sum, this study provides new insights into the molecular mechanism of how Hsp90␣ regulates its extracellular client proteins and also reveals for the first time the function of extracellular Hsp90␣ in promoting tumor angiogenesis.Heat shock protein 90 (Hsp90) 2 is an ATP-dependent molecular chaperone that is ubiquitously expressed and essential for cell viability (1). Unlike other types of chaperones, Hsp90 is not required for the biogenesis of most polypeptides but instead functions in the maintenance of the active state of several conformationally labile signaling proteins (2-4). Many of the Hsp90 client proteins are mutated, chimeric, or overexpressed oncogenic proteins (3). Therefore, the chaperoning function of Hsp90 is subverted to a biochemical buffer for genetic lesions in tumor cells, facilitating the malignant transformations of the cells (3). Hsp90 has emerged as a promising target for cancer therapy (5).There are two isoforms of Hsp90 in the cytosol, referred to as Hsp90␣ and Hsp90␤ (6). Intriguingly, the Hsp90␣ isoform also exists extracellularly (7). Recent studies indicate that extracellular Hsp90␣ is significantly correlated with tumor invasiveness and metastasis (8), and the antibody or impermeable inhibitor of Hsp90␣ can suppress tumor metastasis efficiently in mouse models (9 -11). Furthermore, Hsp90␣ can be detected in the blood of cancer patients, and the level of Hsp90␣ is positively associated with tumor malignancy (9). In addition to tumor cells, extracellular Hsp90␣ has also been identified in neuron cells, dermal fibroblasts, keratinocyte, macrophages, and epithelial cells and participates in neuronal cell migration, wound healing, and viral and bacteria infections (7).Accumulating evidence indicates that extracellular Hsp90␣ plays important roles in both physiological and pathological processes, especially in tumor progression (7). However, the molecular mechanism of how extracellular Hsp90␣ functions is still largely unknown (12). Eustace et al. (8) reported that extracellular Hsp90...

Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses

“…Recent studies have shown that secreted Hsp90a could activate matrix metalloproteinase-2 (MMP2) and thus facilitate maturation of MMP2 for promotion of tumor invasion (11)(12)(13). MMP2 is involved in the breakdown of extracellular matrix in normal physiological processes, and altered MMP2 expression contributes to human disease, including cancer development and progression.…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…As an example, we can refer to EMMPRIN, a class of glycoprotein secreted by tumor cells, which stimulates MMP-2 expression by fibroblasts (Biswas et al, 2010). Nonetheless, factors accounting for the unbalanced regulation of the enzyme are continuously identified; this is the case of the L1CAM adhesion molecule in a model of lung metastasis and of an E3 uniquitin ligase (c-Cbl) (Hauser et al, 2011;Lee and Tsygankov, 2010;Song et al, 2010).…”

Matrix metalloproteinases in head and neck cancer: current perspectives

“…123 Furthermore, extracellular Hsp90α stabilizes and protects MMP2 from degradation in human breast cancer cells through a regulatory mechanism mediated by interaction of Hsp90α with the MMP2 C-terminal hemopexin domain. 124 This interaction enhances the proteolytic activity of MMP2, and thus promotes tumor angiogenesis.…”