Alternative routes for HB-EGF mitogenic effects inhibition

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Siromolot, Andriy
Kolybo, Denys
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Heparin-binding epidermal growth factor–like growth factor (HB-EGF) is a member of the epidermal growth factor family and has a variety of physiological and pathophysiological functions. Also, HB-EGF plays a pivotal role in distinct tumors progression. HB-EGF is highly expressed in certain cancer cells, such as ovarian and breast cancers, that makes it beneficial for the development of antitumor therapeutic agents. Neutralizing agents against HB-EGF can act on two strategies: sterically blocking the binding of HB-EGF with receptors (monoclonal or polyclonal antibodies, diphtheria toxin derivatives) or capable preventing the formation of soluble HB-EGF from proHB-EGF (ectodomain shedding) with MMPs or ADAMs inhibitors. Recombinant analogs of Corynebacterium diphtheriae toxin fragments (subunit B) and it toxoid CRM197 are able to block the binding of fluorescent derivative HB-EGF (HB-EGF-mCherry) with receptors HER1 and HER4 on the surface of A431 and Vero cell lines. It has been shown that immune serum-containing polyclonal antibodies against HB-EGF is able to inhibit HBEGF binding to surface cellular receptors and block the mitogenic activation with HB-EGF of cells by deactivating Ras-MAPK/ERK1/2. Mitogenic activity of sHB-EGF is significantly enhanced by membrane-associated heparan sulfate proteoglycans (HSPG). Interaction of the N-terminal heparin-binding region of HB-EGF with HSPG leads to stabilization of the EGF-like domain of the molecule in complex with the receptor. The ability of heparin to block proliferation of A431 and Vero cells by exogenous HB-EGF has been demonstrated, probably, due to binding with heparin-binding domain of HB-EGF. Moreover, leupeptin and a broad-spectrum metalloproteinase blocker GM6001, and EDTA significantly decrease paracrine activation of cells by HB-EGF. Thus, searching and development of effective neutralizing agents against sHB-EGF is important and perspective research direction for establishing of a new targeted antitumor therapy.
HB-EGF, proHB-EGF, ectodomain shedding, Corynebacterium diphtheriae, HB-EGF-mCherry, Ras-MAPK/ERK1/2, leupeptin, metalloproteinase, antitumor therapy, conference materials
Siromolot A. Alternative routes for HB-EGF mitogenic effects inhibition / A. Siromolot, D. Kolybo // FEBS Open Bio. - 2023. - Vol. 13, Supplement 2 : Together in bioscience for a better future : 47th FEBS Congress, July 8-12, 2023, Tours, France. - P. 63.