title: Cariporide sensitizes leukemic cells to tumor necrosis factor related apoptosis-inducing ligand by up-regulation of death receptor 5 via endoplasmic reticulum stress-CCAAT/enhancer binding protein homologous protein dependent mechanism.
abstract: CCAAT/enhancer binding protein homologous protein (CHOP) expression increases when Na(+)-H(+) exchanger 1 (NHE1) is inhibited. Endoplasmic reticulum (ER) stress has been shown to trigger tumor cell death through CHOP. We therefore hypothesized that NHE1 activity correlates with ER stress and confers pharmaceutical potential to NHE1 inhibitor as an anti-tumor agent. The present study showed that treatment with the NHE1 inhibitor cariporide led to ER stress-induced up-regulation of the death receptor 5 (DR5) which is mediated by CHOP at the transcriptional level. We also determined that ER stress-induced Janus kinase (JNK) activation was responsible for the modulation of CHOP. Combining cariporide with tumor necrosis factor related apoptosis-inducing ligand (TRAIL) led to a significantly enhanced level of apoptosis that was abrogated by siRNA silencing of CHOP. This study provides a potential mechanistic rationale for the use of NHE1 inhibitor in combination with DR5 agonists to induce apoptosis in leukemia.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College , Tianjin , China.
authors.forename: Huawen
authors.initials: H
authors.lastname: Li
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Chang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Lihong
authors.initials: L
authors.lastname: Wang
authors.forename: Weina
authors.initials: W
authors.lastname: Jin
authors.forename: Yani
authors.initials: Y
authors.lastname: Lin
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.forename: Ruojun
authors.initials: R
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Li
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Pang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D013450:Sulfones / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D006146:Guanidines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D013450:Sulfones; D053221:TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; C093373:cariporide
keywords: CHOP; ER stress; NHE1; leukemia