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

  • Authors:
    • Mun-Ock Kim
    • Hyun-Sun Lee
    • Young-Won Chin
    • Dong-Oh Moon
    • Jong-Seog Ahn
  • View Affiliations

  • Published online on: May 5, 2015     https://doi.org/10.3892/or.2015.3948
  • Pages: 139-146
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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, anti‑inflammatory, 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.
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July-2015
Volume 34 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Kim M, Lee H, Chin Y, Moon D and Ahn J: Gartanin induces autophagy through JNK activation which extenuates caspase-dependent apoptosis. Oncol Rep 34: 139-146, 2015.
APA
Kim, M., Lee, H., Chin, Y., Moon, D., & Ahn, J. (2015). Gartanin induces autophagy through JNK activation which extenuates caspase-dependent apoptosis. Oncology Reports, 34, 139-146. https://doi.org/10.3892/or.2015.3948
MLA
Kim, M., Lee, H., Chin, Y., Moon, D., Ahn, J."Gartanin induces autophagy through JNK activation which extenuates caspase-dependent apoptosis". Oncology Reports 34.1 (2015): 139-146.
Chicago
Kim, M., Lee, H., Chin, Y., Moon, D., Ahn, J."Gartanin induces autophagy through JNK activation which extenuates caspase-dependent apoptosis". Oncology Reports 34, no. 1 (2015): 139-146. https://doi.org/10.3892/or.2015.3948