EHHM, a novel phenolic natural product from Livistona chinensis, induces autophagy-related apoptosis in hepatocellular carcinoma cells

Abstract

Hepatocellular carcinoma (HCC) ranks the second cause of cancer-associated mortality worldwide. In the present study, the effects and mechanisms of a new phenolic natural product E-[6′-(5′-hydroxypentyl)tricosyl]-4-hydroxy-3-methoxycinnamate (EHHM) isolated from Livistona chinensis on the growth of HCC cells were investigated. It was observed that EHHM treatment significantly suppressed cell proliferation and colony formation, and induced cell apoptosis via a mitochondria-dependent caspase pathway in HepG2 cells in a time- and dose-dependent manner. Meanwhile, EHHM treatment also led to upregulated expression of autophagy protein 5 (Atg5), Beclin 1 and light chain 3 (LC3)-II proteins, and accumulation of green fluorescent protein-LC3 punctate florescent foci in HCC cells, suggesting that EHHM-induced apoptosis is accompanied by autophagy induction. Western blotting revealed that EHHM-induced autophagy is related to the inhibition of the Akt/mechanistic target of rapamycin/p70 ribosomal protein S6 kinase signaling pathway. Furthermore, treatment with Atg5 small interfering RNA or autophagy inhibitors significantly enhanced EHHM-mediated growth inhibition and apoptotic cell death, indicating that autophagy serves as a self-protective mechanism in EHHM-treated HCC cells, and that combined treatment with EHHM and autophagy inhibitors may be an effective therapeutic strategy for HCC.

Gene and protein expression of mTOR and LC3 in hepatocellular carcinoma, colorectal liver metastasis and “normal” liver tissues

“…Many evidences indicate that miRNAs, by acting either as oncogenes or tumour suppressors, are involved in the process of HCC tumorigenesis and development through the modulation of the autophagic signalling networks [ 54 , 55 ]. miR-181a was reported to repress autophagy in HCC by targeting pro-autophagic protein Atg5, leading to the reduction of apoptosis of HCC cells and acceleration of hepatoma growth [ 56 ]. A significant decrease in miR-7, which induces autophagy by targeting mTOR, was observed in tumour tissue compared to normal tissue suggesting its potential antitumor role in HCC [ 57 ].…”

Targeting Drug Chemo-Resistance in Cancer Using Natural Products

“…A naturally occurring substance, hydroxycinnamates or E-[6'-(5'-hydroxypentyl) tricosyl]-4-hydroxy-3-methoxycinnamate (EHHM), is acquired from Livistona chinensis. It has been reported that autophagy enhances cell longevity in HCC cells administered EHHM; EHHM could therefore be a potentially efficacious strategy for treatment of this tumor [500].…”

“…Quercetin Autophagy [483,611] Resveratrol Autophagy [458,480,492,494,612,637-647] [458,480,494,612,637-641] Anthocyanins Autophagy [499] Hydroxycinnamates Autophagy [500] Berberine Autophagy [486,501,[503][504][505]594,595,648,649] Epigallocatechin-3-gallate Autophagy [534,538,539,650] Curcumin Autophagy [515,[517][518][519][520]522,523,[651][652][653][654] Fangchinoline Autophagy [525] Ginsenosides Autophagy [329,[526][527][528][529][530][531][532][533] Terpenoids Autophagy [358,535,536] Triptolide Autophagy [568,570,655] Betulinic acid Autophagy [547,548]...…”

Antioxidant, Anti‐Inflammatory, and Antidiabetic Activities of Bioactive Compounds from the Fruits of Livistona chinensis Based on Network Pharmacology Prediction

“…FLC was found to be enriched in natural polyphenolics consisting of flavonoids, phenols, lignans, and anthraquinones [8]. Pharmacological studies showed that FLC possessed antioxidant, antitumor, and hepatoprotective effects [7,[9][10][11][12][13][14][15][16][17]. Due to the huge production of FLC and diverse biological activities of the polyphenols in FLC, their potential edibleness needs to be exploited.…”