Curcumin suppresses angiogenesis, invasion and metastasis through inhibiting matrix metalloproteinases in human cancers

Curcumin (diferuloylmethane), an active polyphenol derived from the rhizome of herb Curcuma longa, possesses various pharmacological properties including antioxidant, anti-inflammatory, antiangiogenic and anti-proliferative activities. Pre-clinical and clinical data suggest that curcumin could suppress proliferation, angiogenesis, invasion and metastasis in a wide variety of human malignancies through modulating multiple signaling proteins including matrix metalloproteinases (MMPs). MMPs are a family of zinc-dependent endopeptidases with the capacity to degrade extracellular matrix (ECM) components. MMPs function in degradation of ECM, generation of active peptides and activation of specific growth factors, leading to the remodeling of the tumor microenvironment, which favors the survival of cancer cells. Curcumin suppresses the transcription, secretion and activation of various MMPs. Curcumin also up-regulates the expression of tissue inhibitors of metalloproteinases. The underlying molecular mechanisms by which curcumin regulates MMPs have been delineated. Curcumin modulates multiple signaling pathways including wnt/β-catenin signaling, notch-1 signaling pathway, TGF-β signaling pathway, janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), protein kinase C (PKC), CC motif ligand 2 (CCL2), and transcription factor activator protein-1(AP-1). These signaling pathways directly or indirectly regulate the expression of various MMPs, implicating that curcumin exertsinhibitory effect on MMPs by suppressing these signaling pathways. Overall, curcumin could be developed as an effective MMPs inhibitor in human cancers.