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

• Published in: Oncotarget Vol. 8; no. 15; pp. 25032 - 25045
• Main Authors: Lee, Jihyun, Sohn, Eun Jung, Yoon, Sangwook, Won, Gunho, Kim, Chang Geun, Jung, Ji Hoon, Kim, Sung-Hoon
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 11.04.2017
• Subjects: Abietanes - pharmacology; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Autophagy - drug effects; Cell Line, Tumor; Cell Survival; Endoribonucleases - metabolism; Humans; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; Lung Neoplasms - enzymology; Lung Neoplasms - metabolism; Lysosomes - metabolism; Mesothelioma - enzymology; Mesothelioma - metabolism; Mesothelioma, Malignant; Phosphorylation; Pleural Neoplasms - enzymology; Pleural Neoplasms - metabolism; Protein Binding; Protein Interaction Domains and Motifs; Protein Transport; Protein-Serine-Threonine Kinases - metabolism; Research Paper; Sequestosome-1 Protein - chemistry; Sequestosome-1 Protein - metabolism; Signal Transduction - drug effects; Transcription Factor CHOP - metabolism; autophagy; tanshinone I; IRE1; mesothelioma cells; p62 ΔUBA
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.15336

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.