Cathepsin S Cleaves BAX as a Novel and Therapeutically Important Regulatory Mechanism for Apoptosis

Surinder M Soond, Lyudmila V Savvateeva, Vladimir A Makarov, Neonila V Gorokhovets, Paul A Townsend, Andrey A Zamyatnin

Research output: Contribution to journalArticlepeer-review

Abstract

Certain lysosomal cathepsin proteins have come into focus as being good candidates for therapeutic targeting, based on them being over-expressed in a variety of cancers and based on their regulation of the apoptotic pathway. Here, we report novel findings that highlight the ability of cathepsin S expression to be up-regulated under Paclitaxel-stimulatory conditions in kidney cell lines and it being able to cleave the apoptotic p21 BAX protein in intact cells and in vitro. Consistent with this, we demonstrate that this effect can be abrogated in vitro and in mammalian cells under conditions that utilize dominant-inhibitory cathepsin S expression, cathepsin S expression-knockdown and through the activity of a novel peptide inhibitor, CS-PEP1. Moreover, we report a unique role for cathepsin S in that it can cleave a polyubiquitinated-BAX protein intermediate and is a step that may contribute to down-regulating post-translationally-modified levels of BAX protein. Finally, CS-PEP1 may possess promising activity as a potential anti-cancer therapeutic against chemotherapeutic-resistant Renal Clear Cell Carcinoma kidney cancer cells and for combined uses with therapeutics such as Paclitaxel.

Original languageEnglish
Article number339
Pages (from-to)1-21
Number of pages21
JournalPharmaceutics
Volume13
Issue number3
DOIs
Publication statusPublished - 5 Mar 2021

Keywords

  • Apoptosis
  • BAX
  • Cancer
  • Cathepsins
  • Chemotherapy
  • MOMP
  • Ubiquitination

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

Fingerprint

Dive into the research topics of 'Cathepsin S Cleaves BAX as a Novel and Therapeutically Important Regulatory Mechanism for Apoptosis'. Together they form a unique fingerprint.

Cite this