Abstract
Elevated copper levels in tumor microenvironment are directly correlated to cancer progression in a variety of malignancies. Copper is required in angiogenesis, and promotes the proliferation and metastasis of cancer cells. However, the molecular mechanism of copper in promoting cancer progression remains elusive. Here we report that CD147 serves as a signaling receptor for extracellular Cu2+ in hepatocellular carcinoma (HCC) cells. Cu2+ binds to the extracellular membrane-proximal domain of CD147 and mediates its self-association. Cu2+-mediated self-association of CD147 activates PI3K/Akt signaling pathway leading to the up-regulation of matrix metalloproteinase MMP-2 and MMP-14 in HCC cells. Cu2+-induced CD147 self-association also enhances the ability of HCC cells to stimulate MMP-2 expression from neighboring fibroblasts, as well as increases the invasiveness of HCC cells which is abolished by the copper chelator tetrathiomolybdate. We have mapped the interfaces and identified the key residues of CD147 involved in the Cu2+ induced self-association. The Cu2+ binding deficient CD147 mutant abolishes the stimulating effects of Cu2+ on HCC cells. Our study reveals a novel extracellular signaling role of copper in promoting cancer cell metastasis, which implies that targeting the Cu2+-induced self-association of CD147 is a new strategy for cancer treatment.
Highlights
Copper, an essential transition metal for life, serves as an important structural and catalytic cofactor involved in a diverse series of biochemical processes [1]
Cu2+-induced CD147 selfassociation enhances the ability of hepatocellular carcinoma (HCC) cells to stimulate matrix metalloproteinases (MMP)-2 expression from neighboring fibroblasts, as well as increases the invasiveness of HCC cells which is abolished by the copper chelator tetrathiomolybdate
The membrane-anchored MMP-14 functions as the activator of secreted MMP-2 from its inactive zymogen; and both MMP-2 and MMP-14 promotes cancer cell invasion and metastasis [35, 40, 41], implicating that Cu2+ may modulate the metastatic properties of HCC cells by directly up-regulating MMP-2 and MMP-14 expression
Summary
An essential transition metal for life, serves as an important structural and catalytic cofactor involved in a diverse series of biochemical processes [1]. Copper has long been known to promote angiogenesis [3], and was shown to directly stimulate proliferation and invasion of cancer cells [4, 5]. For other stimulating effects of copper on cancer cells, studies have mainly focused on the roles of intracellular copper as cofactors of enzymes [18]. It was found that 80–90% of intracellular copper are translocated into the extracellular space of the leading edge of endothelial cell projections during angiogenesis [23]. These redistributed copper ions were suggested to bind to and activate yet unknown cell surface receptors or extracellular targets [3]
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