Temporal proteomics reveal specific cell cycle oncoprotein downregulation by p97/VCP inhibition

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Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols

Published on: June 6, 2017

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Feng Wang1, Shan Li1, Nadia Houerbi1

  • 1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

Cell Chemical Biology
|November 30, 2021
PubMed

Insights

p97/VCP inhibitors, unlike proteasome inhibitors, show efficacy in solid tumors by downregulating cell cycle proteins. This targeted cell cycle disruption explains the differential therapeutic effectiveness of p97/VCP inhibitors in colon cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Protein quality control (PQC) pathways are crucial therapeutic targets in cancer.
  • Proteasome or p97/VCP inhibition effectively treats blood tumors, but only p97/VCP inhibitors show efficacy in solid tumors.
  • The molecular basis for this differential efficacy remains unclear.

Purpose of the Study:

  • To investigate the cellular and molecular responses to proteasome and p97/VCP inhibition in HCT116 colon cancer cells.
  • To identify the mechanisms underlying the differential therapeutic effectiveness of these inhibitors in solid tumors.

Main Methods:

  • Temporal proteomics was employed to track cellular responses.
  • Western blot analysis was used to validate protein degradation.

Main Results:

  • Both proteasome and p97/VCP inhibition upregulated general PQC proteins similarly.
  • p97/VCP inhibition, but not proteasome inhibition, led to the downregulation of eleven cell cycle proteins.
  • Cyclin D1 and Securin degradation were validated as proteasome-dependent, not p97/VCP-dependent.

Conclusions:

  • Differential regulation of cell cycle proteins by p97/VCP and proteasome pathways explains the therapeutic efficacy of p97/VCP inhibitors in colon cancer.
  • Targeting cell cycle control via p97/VCP inhibition offers a promising therapeutic strategy for solid tumors.
Keywords:
CB-5083E2F1NMS-873UPCDC-30245anticancercell cyclecyclin D1p97 inhibitorproteasome inhibitorproteomic

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