title: Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Tae Hyong
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Jieun
authors.initials: J
authors.lastname: Song
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Arav Krishnavadan
authors.initials: AK
authors.lastname: Parikh
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Kamalakannan
authors.initials: K
authors.lastname: Palanichamy
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Sung Ok
authors.initials: SO
authors.lastname: Yoon
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Dardinger Neuro-oncology Center, Department of Neurological Surgery, Ohio State University, Columbus, Ohio (T.H.K., J.S., S.-H.K., A.K.P., I.N., B.K., C.-H.K.); Solid Tumor Program at the James Comprehensive Cancer Center, Columbus, Ohio (T.H.K., J.S., A.K.P., C.-H.K.); Center for Biostatistics, Ohio State University, Columbus, Ohio (X.M.); Department of Radiation Oncology, Ohio State University, Columbus, Ohio (K.P.); Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio (J.Y.); Department of Molecular and Cellular Biochemistry, Ohio State University Wexner Medical Center, Columbus, Ohio (S.O.Y.).
authors.forename: Chang-Hyuk
authors.initials: CH
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D016208:Databases, Factual; D004148:Dioxolanes / Q000008:administration & dosage*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D051379:Mice; D054464:Peroxiredoxins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D010881:Piperidones
chemical_list: D000970:Antineoplastic Agents; D004148:Dioxolanes; D054464:Peroxiredoxins; D017382:Reactive Oxygen Species; C515980:PRDX4 protein, human; C498077:piperlongumine; D010881:Piperidones
keywords: Endoplasmic reticulum stress; high-grade glioma; peroxiredoxin 4; piperlongumine; reactive oxygen species