title: Inhibition of JNK3 promotes apoptosis induced by BH3 mimetic S1 in chemoresistant human ovarian cancer cells.
abstract: Previous studies have suggested that the novel BH3 mimetic S1 could induce apoptosis in diverse tumor cell lines through endoplasmic reticulum (ER) stress or mitochondrial cell death pathways. The activation of c-Jun N-terminal kinase (JNK) through inositol requiring enzyme-1 (IRE1) is closely connected to ER stress-induced apoptosis. However, the role of JNK is complex, as there are different JNK subtypes and the function of each subtype is still not entirely clear. Here we found that the mRNA expression of JNK3 was continuously high in S1-treated human ovarian cancer SKOV3/DDP cells using a human unfolded protein response (UPR) pathway PCR array. Pharmacological inhibition of JNK3 increased cell sensitivity to apoptosis induced by S1. Furthermore, inhibition of JNK3 induced accumulation of both acidic compartment and p62, and upregulated ROS production. Our results suggest that JNK3 plays a pro-survival role during ER stress through preventing the block of autophagic flux and reducing oxidative stress in SKOV3/DDP cells. Inhibition of JNK3 may be a potential method to enhance the killing effect of the Bcl-2 inhibitor S1.
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, 130021, People's Republic of China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Yang
authors.forename: Xiyan
authors.initials: X
authors.lastname: Xiang
authors.forename: Meihui
authors.initials: M
authors.lastname: Xia
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.forename: Yao
authors.initials: Y
authors.lastname: Wu
authors.forename: Luyan
authors.initials: L
authors.lastname: Shen
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.forename: Liankun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D040761:Biomimetic Materials / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018716:Molecular Mimicry / Q000187:drug effects* / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D010094:Oxonic Acid / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005641:Tegafur / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D004338:Drug Combinations; D019253:Proto-Oncogene Proteins c-bcl-2; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D048057:Mitogen-Activated Protein Kinase 10
keywords: BH3 mimetic; JNK3; apoptosis; autophagy; endoplasmic reticulum stress; oxidative stress