Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.

Small molecule inhibitors of protein geranylgeranyltransferase-I (GGTase-I) provide a promising type of anticancer drugs. Here, we first report the identification of a novel tetrahydropyridine scaffold compound, P61-E7, and define effects of this compound on pancreatic cancer cells. P61-E7 was ident...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Lai N Chan, Hannah D G Fiji, Masaru Watanabe, Ohyun Kwon, Fuyuhiko Tamanoi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b8a9338ed6314046ab16f6414e1f8b7c
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b8a9338ed6314046ab16f6414e1f8b7c
record_format	dspace
spelling	oai:doaj.org-article:b8a9338ed6314046ab16f6414e1f8b7c2021-11-18T07:36:19ZIdentification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.1932-620310.1371/journal.pone.0026135https://doaj.org/article/b8a9338ed6314046ab16f6414e1f8b7c2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22028818/?tool=EBIhttps://doaj.org/toc/1932-6203Small molecule inhibitors of protein geranylgeranyltransferase-I (GGTase-I) provide a promising type of anticancer drugs. Here, we first report the identification of a novel tetrahydropyridine scaffold compound, P61-E7, and define effects of this compound on pancreatic cancer cells. P61-E7 was identified from a library of allenoate-derived compounds made through phosphine-catalyzed annulation reactions. P61-E7 inhibits protein geranylgeranylation and blocks membrane association of geranylgeranylated proteins. P61-E7 is effective at inhibiting both cell proliferation and cell cycle progression, and it induces high p21(CIP1/WAF1) level in human cancer cells. P61-E7 also increases p27(Kip1) protein level and inhibits phosphorylation of p27(Kip1) on Thr187. We also report that P61-E7 treatment of Panc-1 cells causes cell rounding, disrupts actin cytoskeleton organization, abolishes focal adhesion assembly and inhibits anchorage independent growth. Because the cellular effects observed pointed to the involvement of RhoA, a geranylgeranylated small GTPase protein shown to influence a number of cellular processes including actin stress fiber organization, cell adhesion and cell proliferation, we have evaluated the significance of the inhibition of RhoA geranylgeranylation on the cellular effects of inhibitors of GGTase-I (GGTIs). Stable expression of farnesylated RhoA mutant (RhoA-F) results in partial resistance to the anti-proliferative effect of P61-E7 and prevents induction of p21(CIP1/WAF1) and p27(Kip1) by P61-E7 in Panc-1 cells. Moreover, stable expression of RhoA-F rescues Panc-1 cells from cell rounding and inhibition of focal adhesion formation caused by P61-E7. Taken together, these findings suggest that P61-E7 is a promising GGTI compound and that RhoA is an important target of P61-E7 in Panc-1 pancreatic cancer cells.Lai N ChanHannah D G FijiMasaru WatanabeOhyun KwonFuyuhiko TamanoiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 10, p e26135 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lai N Chan Hannah D G Fiji Masaru Watanabe Ohyun Kwon Fuyuhiko Tamanoi Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.
description	Small molecule inhibitors of protein geranylgeranyltransferase-I (GGTase-I) provide a promising type of anticancer drugs. Here, we first report the identification of a novel tetrahydropyridine scaffold compound, P61-E7, and define effects of this compound on pancreatic cancer cells. P61-E7 was identified from a library of allenoate-derived compounds made through phosphine-catalyzed annulation reactions. P61-E7 inhibits protein geranylgeranylation and blocks membrane association of geranylgeranylated proteins. P61-E7 is effective at inhibiting both cell proliferation and cell cycle progression, and it induces high p21(CIP1/WAF1) level in human cancer cells. P61-E7 also increases p27(Kip1) protein level and inhibits phosphorylation of p27(Kip1) on Thr187. We also report that P61-E7 treatment of Panc-1 cells causes cell rounding, disrupts actin cytoskeleton organization, abolishes focal adhesion assembly and inhibits anchorage independent growth. Because the cellular effects observed pointed to the involvement of RhoA, a geranylgeranylated small GTPase protein shown to influence a number of cellular processes including actin stress fiber organization, cell adhesion and cell proliferation, we have evaluated the significance of the inhibition of RhoA geranylgeranylation on the cellular effects of inhibitors of GGTase-I (GGTIs). Stable expression of farnesylated RhoA mutant (RhoA-F) results in partial resistance to the anti-proliferative effect of P61-E7 and prevents induction of p21(CIP1/WAF1) and p27(Kip1) by P61-E7 in Panc-1 cells. Moreover, stable expression of RhoA-F rescues Panc-1 cells from cell rounding and inhibition of focal adhesion formation caused by P61-E7. Taken together, these findings suggest that P61-E7 is a promising GGTI compound and that RhoA is an important target of P61-E7 in Panc-1 pancreatic cancer cells.
format	article
author	Lai N Chan Hannah D G Fiji Masaru Watanabe Ohyun Kwon Fuyuhiko Tamanoi
author_facet	Lai N Chan Hannah D G Fiji Masaru Watanabe Ohyun Kwon Fuyuhiko Tamanoi
author_sort	Lai N Chan
title	Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.
title_short	Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.
title_full	Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.
title_fullStr	Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.
title_full_unstemmed	Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.
title_sort	identification and characterization of mechanism of action of p61-e7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-i.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/b8a9338ed6314046ab16f6414e1f8b7c
work_keys_str_mv	AT lainchan identificationandcharacterizationofmechanismofactionofp61e7anovelphosphinecatalysisbasedinhibitorofgeranylgeranyltransferasei AT hannahdgfiji identificationandcharacterizationofmechanismofactionofp61e7anovelphosphinecatalysisbasedinhibitorofgeranylgeranyltransferasei AT masaruwatanabe identificationandcharacterizationofmechanismofactionofp61e7anovelphosphinecatalysisbasedinhibitorofgeranylgeranyltransferasei AT ohyunkwon identificationandcharacterizationofmechanismofactionofp61e7anovelphosphinecatalysisbasedinhibitorofgeranylgeranyltransferasei AT fuyuhikotamanoi identificationandcharacterizationofmechanismofactionofp61e7anovelphosphinecatalysisbasedinhibitorofgeranylgeranyltransferasei
_version_	1718423246731214848

Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.

Ejemplares similares