Gartanin induces autophagy through JNK activation which extenuates caspase-dependent apoptosis

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Title
Gartanin induces autophagy through JNK activation which extenuates caspase-dependent apoptosis
Author(s)
Mun-Ock KimHyun Sun Lee; Y W Chin; D O Moon; Jong Seog Ahn
Bibliographic Citation
Oncology Reports, vol. 34, no. 1, pp. 139-146
Publication Year
2015
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Development of novel agents to eradicate liver cancer cells is required for treatment of HCC. Gartanin, a xanthone-type compound isolated from mangosteen, is known to possess potent antioxidant, antiinflammatory, antifungal and antineoplastic properties. In the present study, we investigated the cytotoxic effect of gartanin on HCC and explored the cell death mechanism. We showed that gartanin induced both the extrinsic and intrinsic apoptotic pathways, which were interconnected by caspase-8, -9 and -3 activation. We also provided convincing evidence that gartanin induced autophagy in various cancer cells, as demonstrated by acridine orange staining of intracellular acidic vesicles, the degradation of p62, the conversion of LC3-I to LC3-II and GFP-LC3 punctate fluorescence. Additionally, gartanin induced the formation of typical autophagosomes and autolysosomes and enhanced the degradation rate of intracellular granule(s), including mitochondria. Notably, gartanin-mediated apoptotic cell death was further potentiated by pretreatment with autophagy inhibitors (3-methyladenine and bafilomycin A1) or small interfering RNAs against the autophagic genes (Atg5). These findings suggested that gartanin-mediated autophagic response protected against eventual cell death induced by gartanin. Moreover, gartanin treatment led to phosphorylation/activation of JNK and JNK-dependent phosphorylation of Bcl-2. Importantly, JNK inhibitor (SP600125) inhibited autophagy yet promoted gartanin-induced apoptosis, indicating a key requirement of the JNK-Bcl-2 pathway in the activation of autophagy by gartanin. Taken together, our data suggested that the JNK-Bcl-2 pathway was the critical regulator of gartanin-induced protective autophagy and a potential drug target for chemotherapeutic combination.
Keyword
ApoptosisAutophagyGartaninHepatocellular carcinomaJNK
ISSN
1021-335X
Publisher
Spandidos Publ Ltd
DOI
http://dx.doi.org/10.3892/or.2015.3948
Type
Article
Appears in Collections:
Ochang Branch Institute > Natural Medicine Research Center > 1. Journal Articles
Ochang Branch Institute > Anticancer Agent Research Center > 1. Journal Articles
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