2. Academic Validation
  3. Catalytic inhibitor of Protein Phosphatase 5 activates the extrinsic apoptotic pathway by disrupting complex II in kidney cancer

Catalytic inhibitor of Protein Phosphatase 5 activates the extrinsic apoptotic pathway by disrupting complex II in kidney cancer

  • Cell Chem Biol. 2023 Oct 19;30(10):1223-1234.e12. doi: 10.1016/j.chembiol.2023.06.026.
Elham F Ahanin 1,  Rebecca A Sager 2,  Sarah J Backe 2,  Diana M Dunn 3,  Natela Dushukyan 1,  Adam R Blanden 4,  Nilamber A Mate 5,  Tamie Suzuki 5,  Tyler Anderson 6,  Merin Roy 1,  Jasmeen Oberoi 7,  Chrisostomos Prodromou 8,  Imad Nsouli 2,  Michael Daneshvar 9,  Gennady Bratslavsky 1,  Mark R Woodford 1,  Dimitra Bourboulia 10,  John D Chisholm 11,  Mehdi Mollapour 12
Affiliations

Affiliations

  • 1 Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • 2 Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • 3 Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • 4 Department of Neurology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • 5 Department of Chemistry, Syracuse University, Syracuse, NY 13210, USA.
  • 6 Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; College of Health Professions, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
  • 7 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK.
  • 8 School of Life Sciences, Biochemistry and Biomedicine, University of Sussex, Falmer, Brighton BN1 9QG, UK.
  • 9 Department of Urology, University of California, California, Irvine, CA 92868, USA.
  • 10 Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA. Electronic address: bourmpod@upstate.edu.
  • 11 Department of Chemistry, Syracuse University, Syracuse, NY 13210, USA. Electronic address: jdchisho@syr.edu.
  • 12 Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA. Electronic address: mollapom@upstate.edu.
PMID: 37527661 DOI: 10.1016/j.chembiol.2023.06.026
Abstract

Serine/threonine protein phosphatase-5 (PP5) is involved in tumor progression and survival, making it an attractive therapeutic target. Specific inhibition of protein phosphatases has remained challenging because of their conserved catalytic sites. PP5 contains its regulatory domains within a single polypeptide chain, making it a more desirable target. Here we used an in silico approach to screen and develop a selective inhibitor of PP5. Compound P053 is a competitive inhibitor of PP5 that binds to its catalytic domain and causes Apoptosis in renal Cancer. We further demonstrated that PP5 interacts with FADD, RIPK1, and Caspase 8, components of the extrinsic apoptotic pathway complex II. Specifically, PP5 dephosphorylates and inactivates the death effector protein FADD, preserving complex II integrity and regulating extrinsic Apoptosis. Our data suggests that PP5 promotes renal Cancer survival by suppressing the extrinsic apoptotic pathway. Pharmacologic inhibition of PP5 activates this pathway, presenting a viable therapeutic strategy for renal Cancer.

Keywords

FADD; clear cell renal cell carcinoma; co-chaperone; extrinsic apoptotic pathway; heat shock protein-90; molecular chaperone; serine/threonine phosphatase-5.

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