title: Activation of JNK and IRE1 is critically involved in tanshinone I-induced p62 dependent autophagy in malignant pleural mesothelioma cells: implication of p62 UBA domain.
abstract: The aim of present study is to elucidate autophagic mechanism of tanshinone I (Tan I) in H28 and H2452 mesothelioma cells. Herein, Tan I exerted cytotoxicity with autophagic features of autophagy protein 5 (ATG5)/ microtubule-associated protein 1A/1B-light chain 3II (LC3 II) activation, p62/sequestosome 1 (SQSTM1) accumulation and increased number of LC3II punctae, acridine orange-stained cells and autophagic vacuoles. However, 3-methyladenine (3MA) and NH4Cl increased cytotoxicity in Tan I treated H28 cells. Furthermore, autophagy flux was enhanced in Tan I-treated H28 cells transfected by RFP-GFP-LC3 constructs, with colocalization of GFP-LC3 punctae with LAMP1 or Lysotracker. Interestingly, C-terminal UBA domain is required for Tan 1 induced aggregation of p62 in H28 cells. Notably, Tan I upregulated CCAAT-enhancer-binding protein homologous protein (CHOP), inositol-requiring protein-1 (IRE1) and p-c-Jun N-terminal kinase (p-JNK), but silencing of IRE1 or p62 and JNK inhibitor SP600125 blocked the LC3II accumulation in Tan I-treated H28 cells. Overall, these findings demonstrate that Tan I exerts antitumor activity through a compromise between apoptosis and p62/SQSTM1-dependent autophagy via activation of JNK and IRE 1 in malignant mesothelioma cells.
authors.affiliation: College of Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Sohn
authors.affiliation: College of Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
authors.forename: Sangwook
authors.initials: S
authors.lastname: Yoon
authors.affiliation: College of Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
authors.forename: Gunho
authors.initials: G
authors.lastname: Won
authors.affiliation: College of Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
authors.forename: Chang Geun
authors.initials: CG
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.affiliation: College of Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004722:Endoribonucleases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008654:Mesothelioma / Q000201:enzymology / Q000378:metabolism*; D000086002:Mesothelioma, Malignant; D010766:Phosphorylation; D010997:Pleural Neoplasms / Q000201:enzymology / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D000071456:Sequestosome-1 Protein / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; C497249:DDIT3 protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C021751:tanshinone; D051742:Transcription Factor CHOP; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases
keywords: IRE1; autophagy; mesothelioma cells; p62 ΔUBA; tanshinone I