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.