Stable expression of α1-antitrypsin Portland in MDA-MB-231 cells increased MT1-MMP and MMP-9 levels, but reduced tumour progression.

Abstract

The membrane bound matrix metalloproteinase MT1-MMP plays roles in modulating cell movement, independent of its abilities to remodel the extracellular matrix. Unlike many MMPs, MT1-MMP is activated in the Golgi prior to secretion by a pro-protein convertase, primarily furin. Regulation of the activation of pro-MT1-MMP has been methodically investigated, as altering the level of the active protein has broad implications in both activating other pro-MMPs, including pro-MMP-2, and many subsequent remodelling events. Our previous work in MCF-7 cells has demonstrated that modest, and not extremely high, levels of active MT1-MMP manifests into altered cell morphology and movement. At this low but optimal amount of MT1-MMP protein, changes to MT1-MMP levels are always mirrored by MMP-9 and pERK levels, and always opposite to MMP-2 levels. In this study, stable expression of the furin inhibitor α1-antitrypsin Portland (α1-PDX) in MDA-MB-231 cells increased overall MT1-MMP levels, but cells maintained a 21% proportion of pro-MT1-MMP. The increase in MT1-MMP was mirrored by increases in MMP-9 and pERK, but a decrease in MMP-2. These changes were associated with increased NF-κB transcription. In vitro analysis showed that α1-PDX decreased cell protrusions and migration, and this manifested as decreased tumourigenesis when examined in vivo using a chick CAM assay.

Methyl-CpG-binding protein 2 drives the Furin/TGF-β1/Smad axis to promote epithelial–mesenchymal transition in pancreatic cancer cells

“…TGF-β1 is deemed to be processed by the subtilisin-like proprotein convertase, Furin 5 . In this study, we found that exogenous TGF-β1 could induce Furin expression at both the mRNA and protein levels ( Supplementary Fig.…”

“…Meanwhile, it is generally accepted that the activation of TGF-β1/Smad signaling is critical to induce EMT 3 , 4 . Furin has been reported to promote the migration and invasion abilities of human cancer cells via pro-MT1-MMP and/or pro-TGF-β1 activation 5 , 6 . Furin is a member of the family of subtilisin/kexin-like proprotein convertases (PCs), which contribute to the activation of precursor pro-proteins to become biologically active 7 .…”

Cancer‐associated thrombosis: The search for the holy grail continues

“…It would be of interest to further investigate whether single or co‐expression of the top 3 genes as identified in the patient group experiencing VTE before colorectal cancer diagnosis ( REG4 , SPINK4 , and SERPINA1 ) could serve as a strong predictor of VTE in colorectal cancer patients. Additionally, these three genes encode secretable proteins and therefore future work is required to study if plasma levels could also serve as prognostic biomarkers 58, 59, 60. Furthermore, it would be interesting to investigate if there is a relationship and/or synergism with mutational status of K‐ras, as this is already associated with CAT in colorectal cancer 43.…”

“…Additionally, these three genes encode secretable proteins and therefore future work is required to study if plasma levels could also serve as prognostic biomarkers. [58][59][60] Furthermore, it would be interesting to investigate if there is a relationship and/or synergism with mutational status of K-ras, as this is already associated with CAT in colorectal cancer. 43 Finally, future work may demonstrate that there is a link between the expression profiles in CAT and different subtypes of colon cancer, 61 Overexpression of Reg4 is associated with tumor progression, metastasis and reduced survival.…”

Modulation of RECK levels in Xenopus A6 cells: effects on MT1-MMP, MMP-2 and pERK levels

“…Treatment with the broad spectrum MMP inhibitor BB94 increased MT1-MMP expression, but decreased MMP-2 activation and did not alter pERK protein levels [11]. In mammalian MDA-MB-231 cells, inhibition of pro-MT1-MMP activation elevated global MT1-MMP and pERK levels, but decreased MMP-2 levels [12]. These mammalian cell studies demonstrated that when MT1-MMP levels are altered, pERK and MMP-2 activation levels alter in different ways depending on treatment.…”