RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines

Abstract Ras-specific proteases to degrade RAS within cancer cells are under active development as an innovative strategy to treat tumorigenesis. The naturally occurring biological toxin effector called RAS/RAP1-specific endopeptidase (RRSP) is known to cleave all RAS within a cell, including HRAS,...

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Autores principales:	Caleb K. Stubbs, Marco Biancucci, Vania Vidimar, Karla J. F. Satchell
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5a5574419aae44be93fd81d61bb47664
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spelling	oai:doaj.org-article:5a5574419aae44be93fd81d61bb476642021-12-02T18:03:06ZRAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines10.1038/s41598-021-97422-02045-2322https://doaj.org/article/5a5574419aae44be93fd81d61bb476642021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97422-0https://doaj.org/toc/2045-2322Abstract Ras-specific proteases to degrade RAS within cancer cells are under active development as an innovative strategy to treat tumorigenesis. The naturally occurring biological toxin effector called RAS/RAP1-specific endopeptidase (RRSP) is known to cleave all RAS within a cell, including HRAS, KRAS, NRAS and mutant KRAS G13D. Yet, our understanding of the mechanisms by which RRSP drives growth inhibition are unknown. Here, we demonstrate, using isogenic mouse fibroblasts expressing a single isoform of RAS or mutant KRAS, that RRSP equally inactivates all isoforms of RAS as well as the major oncogenic KRAS mutants. To investigate how RAS processing might lead to varying outcomes in cell fate within cancer cells, we tested RRSP against four colorectal cancer cell lines with a range of cell fates. While cell lines highly susceptible to RRSP (HCT116 and SW1463) undergo apoptosis, RRSP treatment of GP5d and SW620 cells induces G1 cell cycle arrest. In some cell lines, growth effects were dictated by rescued expression of the tumor suppressor protein p27 (Kip1). The ability of RRSP to irreversibly inhibit cancer cell growth highlights the antitumor potential of RRSP, and further warrants investigation as a potential anti-tumor therapeutic.Caleb K. StubbsMarco BiancucciVania VidimarKarla J. F. SatchellNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Caleb K. Stubbs Marco Biancucci Vania Vidimar Karla J. F. Satchell RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines
description	Abstract Ras-specific proteases to degrade RAS within cancer cells are under active development as an innovative strategy to treat tumorigenesis. The naturally occurring biological toxin effector called RAS/RAP1-specific endopeptidase (RRSP) is known to cleave all RAS within a cell, including HRAS, KRAS, NRAS and mutant KRAS G13D. Yet, our understanding of the mechanisms by which RRSP drives growth inhibition are unknown. Here, we demonstrate, using isogenic mouse fibroblasts expressing a single isoform of RAS or mutant KRAS, that RRSP equally inactivates all isoforms of RAS as well as the major oncogenic KRAS mutants. To investigate how RAS processing might lead to varying outcomes in cell fate within cancer cells, we tested RRSP against four colorectal cancer cell lines with a range of cell fates. While cell lines highly susceptible to RRSP (HCT116 and SW1463) undergo apoptosis, RRSP treatment of GP5d and SW620 cells induces G1 cell cycle arrest. In some cell lines, growth effects were dictated by rescued expression of the tumor suppressor protein p27 (Kip1). The ability of RRSP to irreversibly inhibit cancer cell growth highlights the antitumor potential of RRSP, and further warrants investigation as a potential anti-tumor therapeutic.
format	article
author	Caleb K. Stubbs Marco Biancucci Vania Vidimar Karla J. F. Satchell
author_facet	Caleb K. Stubbs Marco Biancucci Vania Vidimar Karla J. F. Satchell
author_sort	Caleb K. Stubbs
title	RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines
title_short	RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines
title_full	RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines
title_fullStr	RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines
title_full_unstemmed	RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines
title_sort	ras specific protease induces irreversible growth arrest via p27 in several kras mutant colorectal cancer cell lines
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5a5574419aae44be93fd81d61bb47664
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RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines

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