Oncotarget

In The News - Press Releases


ONC201 kills breast cancer cells in vitro by targeting mitochondria


FOR IMMEDIATE RELEASE
2018-05-08

The cover for issue 26 of Oncotarget features Figure 8, "Proposed mechanism of action of ONC201," from Greer, et al.

TRAIL, a member of the TNF family of ligands, causes caspase–dependent apoptosis through activation of its receptors, death receptor 4 and DR5.

ONC201 was originally identified as a small molecule that inhibits both Akt and ERK, resulting in dephosphorylation of Foxo3a and thereby induces TRAIL transcription.

Recently, two independent groups, Wafik El Deiry at Fox Chase and Michael Andreeff at MD Anderson,reported that ONC201 induces cell death via cell stress mechanisms, independent of TRAIL transcription. Gene expression profiling analysis revealed that ONC201 induces endoplasmic reticulum (ER) stress or integrated stress response –related genes, such as Activating Transcription Factor 4 (ATF4) and C/EBP–homologous protein (CHOP).

The researchers in Dr. Lipkowitz's group at the Center for Cancer Research in the National Cancer Institute observed that ONC201 kills breast cancer cells via a TRAIL–independent mechanism. Time–lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. They found that ONC201 inhibits mitochondrial respiration and induces mitochondrial structural damage. Moreover, they found ONC201 reduces mitochondrial DNA copy number. Importantly, cells dependent on glycolysis, such as fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mitochondrial DNA were resistant to ONC201. ONC201 induced ATF4 and CHOP in breast cancer cells, and the stress response it was partially dependent on the mitochondrial effects of ONC201.

"Our work identifies a novel mechanism of ONC201 cytotoxicity that is based on the disruption of mitochondrial function, leading to ATP depletion and cell death in cancer cells that are dependent on mitochondrial respiration. Our study also suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201" Dr. Stanley Lipkowitz, Chief, Women's Malignancies Branch, NCI.

Sign up for free Altmetric alerts about this article

DOI - https://doi.org/10.18632/oncotarget.24862

Full text - https://www.oncotarget.com/article/24862/text/

Correspondence to - Stanley Lipkowitz - lipkowis@mail.nih.gov

Keywords - ONC201, breast cancer, mitochondria

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

SoundCloud - https://soundcloud.com/oncotarget
Facebook - https://www.facebook.com/Oncotarget/
Twitter - https://twitter.com/oncotarget
LinkedIn - https://www.linkedin.com/company/oncotarget
Pinterest - https://www.pinterest.com/oncotarget/
Reddit - https://www.reddit.com/user/Oncotarget/

Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

Media Contact
MEDIA@IMPACTJOURNALS.COM
18009220957x105



Copyright © 2020 Impact Journals, LLC
Impact Journals is a registered trademark of Impact Journals, LLC