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RAS specific protease Induces Irreversible Growth Arrest via p27 in several KRAS Mutant Colorectal Cancer cell lines

View ORCID ProfileCaleb K. Stubbs, View ORCID ProfileMarco Biancucci, View ORCID ProfileVania Vidimar, View ORCID ProfileKarla J. F. Satchell
doi: https://doi.org/10.1101/2020.12.08.416578
Caleb K. Stubbs
1Department of Microbiology and Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Marco Biancucci
1Department of Microbiology and Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Vania Vidimar
1Department of Microbiology and Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Karla J. F. Satchell
1Department of Microbiology and Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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  • ORCID record for Karla J. F. Satchell
  • For correspondence: k-satchell@northwestern.edu
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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. In the course of studies developing RRSP as an anti-cancer therapeutic, it was shown that cleavage of total RAS by RRSP results in a range of cell fates from cytotoxicity to moderate growth inhibition. Despite the considerable amount of evidence demonstrating RRSP anti-tumor effects in vivo, our understanding of the mechanisms involved are unknown. Here, we first 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. The cleavage of RAS inhibited phosphorylation of ERK and cell proliferation regardless of the RAS isoform. To investigate further 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 cytotoxic death, RRSP treatment of GP5d cells induces G1 cell cycle arrest, and SW620 cells instead induces growth inhibition through cell senescence. In three of four cell lines tested, growth effects were dictated by rescued expression of the tumor suppressor protein p27 (Kip1). The ability of RRSP to inactivate all RAS and inhibit cancer cell growth through a variety of mechanisms highlights the antitumor potential of RRSP, and further warrants investigation as a potential anti-tumor therapeutic.

Competing Interest Statement

K.J.F.S. has been granted a patent (US 10,829,752 B2) on use of RRSP to treat cancer. K.J.F.S. is a consultant for Buoy Health on topics unrelated to this manuscript. K.J.F.S. has a significant financial interest in Situ Biosciences, LLC, a contract research organization that pursues research unrelated to cancer. C.K.S. is an intern as a scientific and financial advisor for Aspire Capital Partners, LLC, which invests in oncotherapies.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 16, 2021.
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RAS specific protease Induces Irreversible Growth Arrest via p27 in several KRAS Mutant Colorectal Cancer cell lines
Caleb K. Stubbs, Marco Biancucci, Vania Vidimar, Karla J. F. Satchell
bioRxiv 2020.12.08.416578; doi: https://doi.org/10.1101/2020.12.08.416578
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RAS specific protease Induces Irreversible Growth Arrest via p27 in several KRAS Mutant Colorectal Cancer cell lines
Caleb K. Stubbs, Marco Biancucci, Vania Vidimar, Karla J. F. Satchell
bioRxiv 2020.12.08.416578; doi: https://doi.org/10.1101/2020.12.08.416578

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