Combination of Proteasome and Histone Deacetylase Inhibitors Overcomes the Impact of Gain-of-Function p53 Mutations

Xiangbing Meng; Shujie Yang; Yujun Li; Yiyang Li; Eric J Devor; Jianling Bi; Xinhao Wang; Shaikamjad Umesalma; Dawn E Quelle; William H Thiel; Kristina W Thiel; Kimberly K Leslie

doi:10.1155/2018/3810108

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Combination of Proteasome and Histone Deacetylase Inhibitors Overcomes the Impact of Gain-of-Function p53 Mutations

Journal article

Open access

Peer reviewed

Combination of Proteasome and Histone Deacetylase Inhibitors Overcomes the Impact of Gain-of-Function p53 Mutations

Xiangbing Meng, Shujie Yang, Yujun Li, Yiyang Li, Eric J Devor, Jianling Bi, Xinhao Wang, Shaikamjad Umesalma, Dawn E Quelle, William H Thiel, …

Disease markers, Vol.2018, 3810108

2018

DOI: 10.1155/2018/3810108

PMCID: PMC6311857

PMID: 30647797

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https://doi.org/10.1155/2018/3810108View

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Abstract

Mutations in the "guardian of the genome" predominate in solid tumors. In addition to loss of tumor suppressor activity, a specific subset of missense mutations confers additional oncogenic properties. These "gain-of-function" (GOF) mutations portend poor prognosis across cancer types regardless of treatment. Our objective in this study was to identify novel therapeutic opportunities to overcome the deleterious effects of GOF mutants. Using gynecologic cancer cell lines with known mutational status, we established that treatment with a proteasome inhibitor induced cell death in cells with two recurrent GOF mutations (R175H and R248Q), and addition of a histone deacetylase inhibitor (HDACi) enhanced this effect. By contrast, p53-null cancer cells were relatively resistant to the combination. Proteasome inhibition promoted apoptosis of cells with GOF mutations, potentially through induction of the unfolded protein response. In line with the reported hyperstabilization of GOF p53 protein, cells treated with HDACi exhibited reduced levels of p53 protein. Together, these data form the basis for future clinical studies examining therapeutic efficacy in a preselected patient population with GOF mutations.

Cell Survival - drug effects

Cell Proliferation

Proteasome Inhibitors - pharmacology

Down-Regulation

Humans

Panobinostat - pharmacology

Endometrial Neoplasms - metabolism

Tumor Suppressor Protein p53 - metabolism

Bortezomib - pharmacology

Mutation, Missense

Unfolded Protein Response

Tumor Suppressor Protein p53 - genetics

Antineoplastic Combined Chemotherapy Protocols - pharmacology

Gain of Function Mutation - drug effects

Endometrial Neoplasms - genetics

Cell Line, Tumor

Endometrial Neoplasms - drug therapy

Female

Histone Deacetylase Inhibitors - pharmacology

Gene Expression Regulation, Neoplastic - drug effects

Details

Title: Subtitle: Combination of Proteasome and Histone Deacetylase Inhibitors Overcomes the Impact of Gain-of-Function p53 Mutations
Creators: Xiangbing Meng - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA
Shujie Yang - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA
Yujun Li - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa 52242, USA
Yiyang Li - Department of Gynecology, The First Hospital of Jilin University, Changchun City, Jilin Province 130021, China
Eric J Devor - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA
Jianling Bi - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA
Xinhao Wang - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa 52242, USA
Shaikamjad Umesalma - Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242, USA
Dawn E Quelle - Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242, USA
William H Thiel - Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA
Kristina W Thiel - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa 52242, USA
Kimberly K Leslie - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA
Resource Type: Journal article
Publication Details: Disease markers, Vol.2018, 3810108
DOI: 10.1155/2018/3810108
PMID: 30647797
PMCID: PMC6311857
NLM abbreviation: Dis Markers
ISSN: 1875-8630
eISSN: 1875-8630
Publisher: United States
Grant note: P30 CA086862 / NCI NIH HHS
Language: English
Date published: 2018
Academic Unit: Pathology; Obstetrics and Gynecology; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9983931817302771

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