Selective matrix metalloproteinase (MMP) inhibitors in cancer therapy

Hypothetical function of mT1-mmP homodimer and heterodimer formation on proteolytic activity, cell migration and proliferation: The hemopexin (PeX) domain of mT1-mmP interacts with CD44 or an unknown protein (heterodimer) at the cell surface, which signals for cell migration through maPK, PI3K and rac pathways, possibly involving initial activation of receptor tyrosine kinases (rTK) and ras. maPK also signals to the nucleus leading to epithelial-mesenchymal transition (emT) by enhancing Twist-1 and Snail activation. enhanced activity of PI3K or Wnt signaling pathways leads to inhibition of GSK-3β, an important regulator for β-catenin and Snail. Inhibition of GSK-3β results in transcriptional downregulation of IκB, and hence enhances activity of nFκB and subsequent Snail expression. mT1-mmP also forms homodimers at the cell surface which is critically important for the enzymatic activity of mT1-mmP. Cleavage of cell-cell adherens junction molecule, e-cadherin by mT1-mmP leads to dissociation of the e-cadherin-β-catenin complex and results in β-catenin relocation. β-catenin relocation to nucleus serves as a transcription factor along with TCF to upregulate gene expression for cell proliferation. Positive and negative feedback loops involving mT1-mmP and e-cadherin maintain the aggressive character of emT cancer cells. mT1-mmP also cleaves prommP-2, most of extracellular matrix (eCm) components, growth factors, and cell surface receptors. Both proteolytic activity and non-proteolytic activity of mT1-mmP coordinate to promote cancer emT. other control mechanisms for mT1-mmP function in cells involve enzyme activation by furin in the trans Golgi network and an elaborate endocytic pathway (not shown).

Publication

Selective matrix metalloproteinase (MMP) inhibitors in cancer therapy. () Stanley Zucker, et al. Cancer Biol Ther. ;8(24):2371-2373. Figure: F1. All organisms Mus musculus Homo sapiens Danio rerio

Disease mentions