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Published March 17, 2022 | Accepted Version + Supplemental Material
Journal Article Open

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

  • 1. ROR icon California Institute of Technology

Abstract

Targeting protein quality control (PQC) pathways using proteasome or p97/VCP inhibition can effectively treat blood tumors. However, in solid tumors, only p97/VCP inhibitors are effective. To probe this difference in efficacy, we tracked HCT116 colon cancer cells using temporal proteomics to define the cellular and molecular responses to proteasome and p97 inhibition. Proteins involved in general PQC pathways were similarly upregulated by both treatments, suggesting that the proteotoxic stress caused by inhibitors does not explain the differential therapeutic effectiveness. Unexpectedly, proteins specifically dysregulated by two p97 inhibitors are involved in cell cycle control. Indeed, eleven cell cycle proteins were downregulated by p97 inhibition but not by proteasome inhibition. Western blot analysis validated the degradation of cyclin D1 and Securin, which depends on proteasome but not on p97. Differing regulation of cell cycle proteins by p97 and the proteasome may, therefore, explain the therapeutic efficacy of p97 inhibitors in colon cancer.

Additional Information

© 2021 Elsevier. Received 22 April 2021, Revised 3 August 2021, Accepted 2 November 2021, Available online 29 November 2021. This work was supported in part with funds from the National Institute of Neurological Disorders and Stroke, R01NS100815 and R01NS102279. Author contributions. F.W. wrote the manuscript. F.W. and S.L. performed the cellular assays and proteomics studies. N.H. performed analysis and improved language. T.-F.C. supervised the project. Data and code availability. All relevant data generated during this study are included in the article and the supplemental information. The mass spectrometry raw data related to Figures 1A–1D are deposited to the ProteomeXchance Consortium (https://www.ebi.ac.uk/pride/) via the PRIDE repository with the dataset identifier PXD025094 and 10.6019/PXD025094". The mass spectrometry raw data related to Figures 1E–1G with dataset identifier PXD025167 and 10.6019/PXD025167". The mass spectrometry raw data related to Figure 2 with dataset identifier PXD025225 and 10.6019/PXD025225". This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. The authors declare no competing interests.

Attached Files

Accepted Version - nihms-1761463.pdf

Supplemental Material - 1-s2.0-S2451945621004827-mmc1.pdf

Supplemental Material - 1-s2.0-S2451945621004827-mmc2.xlsx

Supplemental Material - 1-s2.0-S2451945621004827-mmc3.xlsx

Supplemental Material - 1-s2.0-S2451945621004827-mmc4.xlsx

Supplemental Material - 1-s2.0-S2451945621004827-mmc5.xlsx

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Additional details

Created:
August 22, 2023
Modified:
December 22, 2023