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

Wang, Feng and Li, Shan and Houerbi, Nadia and Chou, Tsui-Fen (2021) Temporal proteomics reveal specific cell cycle oncoprotein downregulation by p97/VCP inhibition. Cell Chemical Biology . ISSN 2451-9456. doi:10.1016/j.chembiol.2021.11.005. (In Press) https://resolver.caltech.edu/CaltechAUTHORS:20211201-482793884

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.chembiol.2021.11.005DOIArticle
ORCID:
AuthorORCID
Li, Shan0000-0002-0829-1821
Chou, Tsui-Fen0000-0003-2410-2186
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.
Funders:
Funding AgencyGrant Number
NIHR01NS100815
NIHR01NS102279
Subject Keywords:p97 inhibitor; proteasome inhibitor; E2F1; cyclin D1; cell cycle; anticancer; proteomic; CB-5083; NMS-873; UPCDC-30245
DOI:10.1016/j.chembiol.2021.11.005
Record Number:CaltechAUTHORS:20211201-482793884
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211201-482793884
Official Citation:Feng Wang, Shan Li, Nadia Houerbi, Tsui-Fen Chou, Temporal proteomics reveal specific cell cycle oncoprotein downregulation by p97/VCP inhibition, Cell Chemical Biology, 2021, , ISSN 2451-9456, https://doi.org/10.1016/j.chembiol.2021.11.005.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112133
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:01 Dec 2021 08:47
Last Modified:01 Dec 2021 16:55

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