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Role of Dopamine Receptors in the Anticancer Activity of ONC201

Neoplasia (New York, N.Y.), 2018-01, Vol.20 (1), p.80-91 [Peer Reviewed Journal]

2018 The Authors ;Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved. ;Copyright Neoplasia Press Jan 2018 ;ISSN: 1476-5586 ;ISSN: 1522-8002 ;EISSN: 1476-5586 ;DOI: 10.1016/j.neo.2017.10.002 ;PMID: 29216597

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Title:
Role of Dopamine Receptors in the Anticancer Activity of ONC201
Author: Kline, Christina Leah B. ; Ralff, Marie D. ; Lulla, Amriti R. ; Wagner, Jessica M. ; Abbosh, Phillip H. ; Dicker, David T. ; Allen, Joshua E. ; El-Deiry, Wafik S.
Subjects: Antineoplastic Agents - pharmacology ; Antitumor activity ; Apoptosis - drug effects ; Cancer ; Cell Line, Tumor ; Cell number ; Cell Survival - drug effects ; Cellular stress response ; CRISPR ; Cytotoxicity ; Dopamine ; Dopamine D1 receptors ; Dopamine D2 receptors ; Dopamine D3 receptors ; Dopamine D5 receptors ; Dopamine receptors ; Drug Resistance, Neoplasm ; Gene Expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Knockout Techniques ; Heterocyclic Compounds, 4 or More Rings - pharmacology ; Humans ; Imidazoles ; Neoplasms - genetics ; Neoplasms - metabolism ; Poly(ADP-ribose) polymerase ; Polymerase chain reaction ; Pyridines ; Pyrimidines ; Receptors, Dopamine - genetics ; Receptors, Dopamine - metabolism ; Receptors, Dopamine D2 - genetics ; Receptors, Dopamine D2 - metabolism ; Receptors, Dopamine D3 - genetics ; Receptors, Dopamine D3 - metabolism ; Receptors, Dopamine D5 - genetics ; Receptors, Dopamine D5 - metabolism ; RNA, Small Interfering - genetics ; siRNA ; Stress response ; Tumor cell lines
Is Part Of: Neoplasia (New York, N.Y.), 2018-01, Vol.20 (1), p.80-91
Description: ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response. Its promising safety profile and broad-spectrum efficacy in vitro have been confirmed in Phase I/II trials in several advanced malignancies. Binding and reporter assays have shown that ONC201 is a selective antagonist of the dopamine D2-like receptors, specifically, DRD2 and DRD3. We hypothesized that ONC201’s interaction with DRD2 plays a role in ONC201’s anticancer effects. Using cBioportal and quantitative reverse-transcription polymerase chain reaction analyses, we confirmed that DRD2 is expressed in different cancer cell types in a cell type–specific manner. On the other hand, DRD3 was generally not detectable. Overexpressing DRD2 in cells with low DRD2 levels increased ONC201-induced PARP cleavage, which was preceded and correlated with an increase in ONC201-induced CHOP mRNA expression. On the other hand, knocking out DRD2 using CRISPR/Cas9 in three cancer cell lines was not sufficient to abrogate ONC201’s anticancer effects. Although ONC201’s anticancer activity was not dependent on DRD2 expression in the cancer cell types tested, we assessed the cytotoxic potential of DRD2 blockade. Transient DRD2 knockdown in HCT116 cells activated the integrated stress response and reduced cell number. Pharmacological antagonism of DRD2 significantly reduced cell viability. Thus, we demonstrate in this study that disrupting dopamine receptor expression and activity can have cytotoxic effects that may at least be in part due to the activation of the integrated stress response. On the other hand, ONC201’s anticancer activity goes beyond its ability to antagonize DRD2, potentially due to ONC201’s ability to activate other pathways that are independent of DRD2. Nevertheless, blocking the dopamine D1-like receptor DRD5 via siRNA or the use of a pharmacological antagonist promoted ONC201-induced anticancer activity.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 1476-5586
ISSN: 1522-8002
EISSN: 1476-5586
DOI: 10.1016/j.neo.2017.10.002
PMID: 29216597
Source: MEDLINE
PubMed Central
DOAJ Directory of Open Access Journals

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Role of Dopamine Receptors in the Anticancer Activity of ONC201

2018 The Authors ;Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved. ;Copyright Neoplasia Press Jan 2018 ;ISSN: 1476-5586 ;ISSN: 1522-8002 ;EISSN: 1476-5586 ;DOI: 10.1016/j.neo.2017.10.002 ;PMID: 29216597

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