Transition state analogue of MTAP extends lifespan of APCMin/+ mice

Abstract A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5′-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5′-Methylthioadenosine (MTA), the...

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Autores principales:	Ross S. Firestone, Mu Feng, Indranil Basu, Karina Peregrina, Leonard H. Augenlicht, Vern L. Schramm
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/635250f8ffb640bcabea407fc2831f58
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spelling	oai:doaj.org-article:635250f8ffb640bcabea407fc2831f582021-12-02T16:45:47ZTransition state analogue of MTAP extends lifespan of APCMin/+ mice10.1038/s41598-021-87734-62045-2322https://doaj.org/article/635250f8ffb640bcabea407fc2831f582021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87734-6https://doaj.org/toc/2045-2322Abstract A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5′-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5′-Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled by MTAP to S-adenosyl-l-methionine (SAM) via salvage pathways. MTDIA treatment causes accumulation of MTA, which inhibits growth of human head and neck (FaDu) and lung (H359, A549) cancers in immunocompromised mouse models. We investigated the efficacy of oral MTDIA as an anti-cancer therapeutic for intestinal adenomas in immunocompetent APCMin/+ mice, a murine model of human Familial Adenomatous Polyposis. Tumors in APCMin/+ mice were decreased in size by MTDIA treatment, resulting in markedly improved anemia and doubling of mouse lifespan. Metabolomic analysis of treated mice showed no changes in polyamine, methionine, SAM or ATP levels when compared with control mice but indicated an increase in MTA, the MTAP substrate. Generation of an MTDIA-resistant cell line in culture showed a four-fold amplification of the methionine adenosyl transferase (MAT2A) locus and expression of this enzyme. MAT2A is downstream of MTAP action and catalyzes synthesis of the SAM necessary for methylation reactions. Immunohistochemical analysis of treated mouse intestinal tissue demonstrated a decrease in symmetric dimethylarginine, a PRMT5-catalyzed modification. The anti-cancer effects of MTDIA indicate that increased cellular MTA inhibits PRMT5-mediated methylations resulting in attenuated tumor growth. Oral dosing of MTDIA as monotherapy has potential for delaying the onset and progression of colorectal cancers in Familial Adenomatous Polyposis (FAP) as well as residual duodenal tumors in FAP patients following colectomy. MTDIA causes a physiologic inactivation of MTAP and may also have efficacy in combination with inhibitors of MAT2A or PRMT5, known synthetic-lethal interactions in MTAP −/− cancer cell lines.Ross S. FirestoneMu FengIndranil BasuKarina PeregrinaLeonard H. AugenlichtVern L. SchrammNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ross S. Firestone Mu Feng Indranil Basu Karina Peregrina Leonard H. Augenlicht Vern L. Schramm Transition state analogue of MTAP extends lifespan of APCMin/+ mice
description	Abstract A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5′-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5′-Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled by MTAP to S-adenosyl-l-methionine (SAM) via salvage pathways. MTDIA treatment causes accumulation of MTA, which inhibits growth of human head and neck (FaDu) and lung (H359, A549) cancers in immunocompromised mouse models. We investigated the efficacy of oral MTDIA as an anti-cancer therapeutic for intestinal adenomas in immunocompetent APCMin/+ mice, a murine model of human Familial Adenomatous Polyposis. Tumors in APCMin/+ mice were decreased in size by MTDIA treatment, resulting in markedly improved anemia and doubling of mouse lifespan. Metabolomic analysis of treated mice showed no changes in polyamine, methionine, SAM or ATP levels when compared with control mice but indicated an increase in MTA, the MTAP substrate. Generation of an MTDIA-resistant cell line in culture showed a four-fold amplification of the methionine adenosyl transferase (MAT2A) locus and expression of this enzyme. MAT2A is downstream of MTAP action and catalyzes synthesis of the SAM necessary for methylation reactions. Immunohistochemical analysis of treated mouse intestinal tissue demonstrated a decrease in symmetric dimethylarginine, a PRMT5-catalyzed modification. The anti-cancer effects of MTDIA indicate that increased cellular MTA inhibits PRMT5-mediated methylations resulting in attenuated tumor growth. Oral dosing of MTDIA as monotherapy has potential for delaying the onset and progression of colorectal cancers in Familial Adenomatous Polyposis (FAP) as well as residual duodenal tumors in FAP patients following colectomy. MTDIA causes a physiologic inactivation of MTAP and may also have efficacy in combination with inhibitors of MAT2A or PRMT5, known synthetic-lethal interactions in MTAP −/− cancer cell lines.
format	article
author	Ross S. Firestone Mu Feng Indranil Basu Karina Peregrina Leonard H. Augenlicht Vern L. Schramm
author_facet	Ross S. Firestone Mu Feng Indranil Basu Karina Peregrina Leonard H. Augenlicht Vern L. Schramm
author_sort	Ross S. Firestone
title	Transition state analogue of MTAP extends lifespan of APCMin/+ mice
title_short	Transition state analogue of MTAP extends lifespan of APCMin/+ mice
title_full	Transition state analogue of MTAP extends lifespan of APCMin/+ mice
title_fullStr	Transition state analogue of MTAP extends lifespan of APCMin/+ mice
title_full_unstemmed	Transition state analogue of MTAP extends lifespan of APCMin/+ mice
title_sort	transition state analogue of mtap extends lifespan of apcmin/+ mice
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/635250f8ffb640bcabea407fc2831f58
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Transition state analogue of MTAP extends lifespan of APCMin/+ mice

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