Abstract. Sedanolide (SN), a phthalide-like compound from celery seed oil, possesses antioxidant effects. However, the effect of SN on cell death in human liver cancer cells has yet to be determined. In this study, cell viability determination, monodansylcadaverine (MDC) fluorescent staining and immunoblot analysis were performed to determine autophagy induction and autophagy-induced protein expression changes via molecular examination after human liver cancer (J5) cells were treated with SN. Our studies demonstrate that SN suppressed J5 cell viability by inducing autophagy. Phosphoinositide 3-kinase (PI3K)-I, mammalian target of rapamycin (mTOR) and Akt protein levels decreased, whereas PI3K-III, LC3-II and Beclin-1 protein levels increased following SN treatment in J5 cells. In addition, SN treatment upregulated nuclear p53 and damage-regulated autophagy modulator (DRAM) and downregulated cytosolic p53 and Tp53-induced glycolysis and apoptosis regulator (TIGAR) expression in J5 cells. Furthermore, the cytosolic phosphorylation of inhibitor of kappa B (IκB) and nuclear p65 and the DNA-binding activity of NF-κB increased after SN treatment.These results suggest that SN induces J5 cell autophagy by regulating PI3K, p53 and NF-κB autophagy-associated signaling pathways in J5 cells. IntroductionHuman hepatocellular carcinoma (HCC) is one of the most common malignant tumors and a significant cause of mortality in several regions of Africa and Asia (1,2). Triggering cancer cell death to reduce cancer cell number and inhibiting cancer cell proliferation by phytochemicals or chemotherapeutic agents represent some of the most effective current anticancer strategies (3). Cell death can occur through one of three pathways: necrosis, apoptosis or autophagy (4).Autophagy is induced by various physiological conditions, such as mitochondrial damage, protein aggregation, pathogen infection and nutrient starvation (5,6). Autophagy is a multi-step cellular pathophysiological program, including initiation (pre-autophagosome formation), autophagosome formation, maturation and degradation (7). In these steps, phosphoinositide 3-kinases (PI3Ks) play key regulatory roles in many cellular processes, including cell survival, proliferation and differentiation (8-10). Both class I PI3K (PI3K-I)/Akt/ mammalian target of rapamycin (mTOR) and Beclin-1/class III PI3K (PI3K-III)/LC3-II signaling pathways are involved in pre-autophagosome formation (11-14). Cytosolic and nuclear p53, damage-regulated autophagy modulator (DRAM) and the p53-induced glycolysis and apoptosis regulator (TIGAR) are involved in autophagosome formation (15). In addition, p53 initiates a cascade of starvation signals and triggers a starvation-like response by inhibiting mTOR (16). Furthermore, p53 activates both the DRAM and PI3K-III pathways upon autophagosome formation (15). Phytochemicals or chemical agents that regulate p53-and PI3K-mediated autophagy induction could serve as a potential starting point for novel methods of cancer prevention and treatment.The transc...

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