Tigilanol tiglate-induced changes in secretome profiles alter c-Met phosphorylation and cell surface protein expression in H357 head and neck cancer cells

Antwi, Frank D., Awad, Tufaha, Larin, Meghan, Heesom, Kate, Lewis, Phil, Reddell, Paul, Poghosyan, Zaruhi ORCID: https://orcid.org/0000-0003-4966-7618, Dewitt, Sharon ORCID: https://orcid.org/0000-0001-8169-8241, Moseley, Ryan ORCID: https://orcid.org/0000-0002-2812-6735 and Knäuper, Vera ORCID: https://orcid.org/0000-0002-3965-9924 2024. Tigilanol tiglate-induced changes in secretome profiles alter c-Met phosphorylation and cell surface protein expression in H357 head and neck cancer cells. Cells 13 (11) , 982. 10.3390/cells13110982

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Abstract

Tigilanol tiglate (TT, also known as EBC-46) is a novel, plant-derived diterpene ester possessing anticancer and wound-healing properties. Here, we show that TT-evoked PKC-dependent S985 phosphorylation of the tyrosine kinase MET leads to subsequent degradation of tyrosine phosphorylated p-Y1003 and p-Y1234/5 MET species. PKC inhibition with BIM-1 blocked S985 phosphorylation of MET and led to MET cell surface accumulation. Treatment with metalloproteinase inhibitors prevented MET-ECD release into cell culture media, which was also blocked by PKC inhibitors. Furthermore, unbiased secretome analysis, performed using TMT-technology, identified additional targets of TT-dependent release of cell surface proteins from H357 head and neck cancer cells. We confirm that the MET co-signalling receptor syndecan-1 was cleaved from the cell surface in response to TT treatment. This was accompanied by rapid cleavage of the cellular junction adhesion protein Nectin-1 and the nerve growth factor receptor NGFRp75/TNFR16. These findings, that TT is a novel negative regulator of protumorigenic c-MET and NGFRp75/TNFR16 signalling, as well as regulating Nectin-1-mediated cell adhesion, further contribute to our understanding of the mode of action and efficacy of TT in the treatment of solid tumours.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry Medicine
Publisher:	MDPI
ISSN:	2073-4409
Date of First Compliant Deposit:	5 June 2024
Date of Acceptance:	1 June 2024
Last Modified:	01 Jul 2024 13:47
URI:	https://orca.cardiff.ac.uk/id/eprint/169487

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