Abstract
Sugar-based molecules such as heparins or natural heparan sulfate polysaccharides have been developed and widely studied for controlling heparanase (HPSE) enzymatic activity, a key player in extracellular matrix remodelling during cancer pathogenesis. However, non-enzymatic functions of HPSE have also been described in tumour mechanisms. Given their versatile properties, we hypothesized that sugar-based inhibitors may interfere with enzymatic but also non-enzymatic HPSE activities. In this work, we assessed the effects of an original marine λ-carrageenan derived oligosaccharide (λ-CO) we previously described, along with those of its native counterpart and heparins, on cell viability, proliferation, migration, and invasion of MDA-MB-231 breast cancer cells but also of sh-MDA-MB-231 cells, in which the expression of HPSE was selectively downregulated. We observed no cytotoxic and no anti-proliferative effects of our compounds but surprisingly λ-CO was the most efficient to reduce cell migration and invasion compared with heparins, and in a HPSE-dependent manner. We provided evidence that λ-CO tightly controlled a HPSE/MMP-14/MMP-2 axis, leading to reduced MMP-2 activity. Altogether, this study highlights λ-CO as a potent HPSE “modulator” capable of reducing not only the enzymatic activity of HPSE but also the functions controlled by the HPSE levels.
Highlights
In previous studies [22,27], we described the production of low molecular weight heparin derivative (LMWH) of 5.1 kDa by the radical depolymerisation technic from an unfractionated commercial heparin (UFH), a standard for in vitro enzymatic inhibition of HPSE [22,27]
We demonstrated that depolymerisation of the native λ-CAR completely reversed its unfavourable properties towards Triple negative breast cancer (TNBC) cells motility
We found that TNBC treatment with λ-carrageenan derived oligosaccharide (λ-CO) reduced HPSE level and trafficking. λ-CO downregulated additional factors linked with extracellular matrix (ECM) remodelling and breast cancer progression, in particular MT1-matrix metalloproteinases (MMPs) and its direct target MMP-2, and our data suggest that HPSE protein level acts as an orchestrator of MMP-2 activation
Summary
Rémi Cousin 1 , Hugo Groult 1 , Chanez Manseur 1 , Romain Ferru-Clément 1 , Mario Gani 1 , Rachel Havret 1 , Claire Toucheteau 1 , Grégoire Prunier 1 , Béatrice Colin 1 , Franck Morel 2 , Jean-Marie Piot 1 , Isabelle Lanneluc 1 , Kévin Baranger 3 , Thierry Maugard 1 and Ingrid Fruitier-Arnaudin 1, *.
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