Oncotarget

Research Papers:

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

Jihyun Lee, Eun Jung Sohn, Sangwook Yoon, Gunho Won, Chang Geun Kim, Ji Hoon Jung, Sung-Hoon Kim _

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Oncotarget. 2017; 8:25032-25045. https://doi.org/10.18632/oncotarget.15336

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Abstract

Jihyun Lee1,*, Eun Jung Sohn1,*, Sangwook Yoon1, Gunho Won1, Chang Geun Kim1, Ji Hoon Jung1, Sung-Hoon Kim1

1College of Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, 130-701, Republic of Korea

*These authors have contributed equally to this work

Correspondence to:

Sung-Hoon Kim, email: sungkim7@khu.ac.kr

Keywords: tanshinone I, autophagy, p62 ΔUBA, IRE1, mesothelioma cells

Received: October 27, 2016     Accepted: January 16, 2017     Published: February 15, 2017

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.


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