Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells

Piperlongumine, a natural plant product, kills multiple cancer types with little effect on normal cells. Piperlongumine raises intracellular levels of reactive oxygen species (ROS), a phenomenon that may underlie the cancer-cell killing. Although these findings suggest that piperlongumine could be u...

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Published in:	Neuro-oncology (Charlottesville, Va.) Vol. 16; no. 10; pp. 1354 - 1364
Main Authors:	Kim, Tae Hyong, Song, Jieun, Kim, Sung-Hak, Parikh, Arav Krishnavadan, Mo, Xiaokui, Palanichamy, Kamalakannan, Kaur, Balveen, Yu, Jianhua, Yoon, Sung Ok, Nakano, Ichiro, Kwon, Chang-Hyuk
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 01-10-2014
Subjects:	Animals Antineoplastic Agents - administration & dosage Apoptosis - drug effects Basic and Translational Investigations Brain Neoplasms - drug therapy Brain Neoplasms - metabolism Brain Neoplasms - mortality Databases, Factual Dioxolanes - administration & dosage Endoplasmic Reticulum Stress - drug effects Glioma - drug therapy Glioma - metabolism Glioma - mortality Humans Mice Peroxiredoxins - metabolism Reactive Oxygen Species - metabolism Survival Analysis Tumor Cells, Cultured piperlongumine high-grade glioma peroxiredoxin 4 reactive oxygen species Endoplasmic reticulum stress
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Summary:	Piperlongumine, a natural plant product, kills multiple cancer types with little effect on normal cells. Piperlongumine raises intracellular levels of reactive oxygen species (ROS), a phenomenon that may underlie the cancer-cell killing. Although these findings suggest that piperlongumine could be useful for treating cancers, the mechanism by which the drug selectively kills cancer cells remains unknown. We treated multiple high-grade glioma (HGG) sphere cultures with piperlongumine and assessed its effects on ROS and cell-growth levels as well as changes in downstream signaling. We also examined the levels of putative piperlongumine targets and their roles in HGG cell growth. Piperlongumine treatment increased ROS levels and preferentially killed HGG cells with little effect in normal brain cells. Piperlongumine reportedly increases ROS levels after interactions with several redox regulators. We found that HGG cells expressed higher levels of the putative piperlongumine targets than did normal neural stem cells (NSCs). Furthermore, piperlongumine treatment in HGG cells, but not in normal NSCs, increased oxidative inactivation of peroxiredoxin 4 (PRDX4), an ROS-reducing enzyme that is overexpressed in HGGs and facilitates proper protein folding in the endoplasmic reticulum (ER). Moreover, piperlongumine exacerbated intracellular ER stress, an effect that was mimicked by suppressing PRDX4 expression. Our results reveal that the mechanism by which piperlongumine preferentially kills HGG cells involves PRDX4 inactivation, thereby inducing ER stress. Therefore, piperlongumine treatment could be considered as a novel therapeutic option for HGG treatment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 T. H. Kim and J. Song contributed equally to this article.
ISSN:	1522-8517 1523-5866
DOI:	10.1093/neuonc/nou088