Curcumin induces Mitochondrial Apoptosis in Human Hepatoma Cells through BCLAF1-mediated Modulation of PI3K/AKT/GSK-3β Signaling

Abstract

Curcumin is a yellow pigment extracted from the rhizome of turmeric, a traditional Chinese medicine. Here, we tested the hypothesis that curcumin-mediated downregulation of BCLAF1 triggers mitochondrial apoptosis in hepatoma cells by inhibiting PI3K/AKT/GSK-3β signaling. Treatment of the human hepatoma cell lines, HepG2 and SK-Hep-1, with various concentrations of curcumin revealed a time-dependent and concentration-dependent inhibition of cell proliferation, increased apoptosis, cell cycle arrest at the G0/G1 phase, reduced mitochondrial membrane potential, and reduced expression levels of PI3K, p-PI3K, AKT, p-AKT, GSK-3β, and p-GSK-3β. Additionally, curcumin suppressed the levels of apoptotic factors after treating the cells with LY294002, a PI3K inhibitor. Curcumin also suppressed the expression of BCLAF1. Treating stable BCLAF1 knockout HepG2 and SK-Hep-1 cells with curcumin further enhanced apoptosis and increased the number of cells in G0/G1 cell cycle arrest, while inhibiting the downregulation of PI3K/AKT/GSK-3β pathway-related proteins. Treatment of a nude mouse xenograft model bearing HepG2 cells with curcumin inhibited tumor growth, disrupted the cellular structure of the tumor tissue, and suppressed the expression of BCLAF1 and PI3K/AKT/GSK-3β proteins. In summary, our in vitro and in vivo analyses show that curcumin downregulates BCLAF1 expression, inhibits the activation of the PI3K/AKT/GSK-3β pathway, and triggers mitochondrial apoptosis in HCC. These findings uncover a potential therapeutic strategy leveraging the antitumor effects of curcumin against HCC.

Targeted Pyroptosis Is a Potential Therapeutic Strategy for Cancer

“…signaling pathway [169][170][171] 17β-estradiol Induces the activation of NLRP3 infammasome [173] Increases FOXO3 phosphorylation, induces oxidative stress, and downregulates IL-6/STAT3 signaling [174,175] Berberine Induces caspase-1-dependent pyroptosis [176] Regulates NF-κB/p65 pathway and induces adenosine AMPK-mediatedcaspase-dependent apoptosis [177,178] Euxanthone Promotes pyroptosis in a caspase-dependent manner [156] Alpinumisofavone Induces NLRP3 infammasome-mediated pyroptosis [157] Breast cancer Polydatin Downregulates the JAK2 and STAT3 levels [184] Suppresses the ROS/PI3K/Akt pathway [185] Cisplatin Activates the NLRP3/caspase-1/GSDMD pathway [186] Downregulates the PI3K/Akt/mTOR signaling pathway [187] Table 1: Continued.…”

“…In addition, CUR may inhibit the growth of HepG2 cells by promoting the P53-dependent apoptosis [169]. Moreover, CUR triggers mitochondrial apoptosis in HCC cells by inhibiting the PI3K/Akt/glycogen synthase kinase-3β (GSK-3β) signaling pathway [170,171]. 17β-estradiol (E2) is a kind of hormonally active compounds [172].…”

Plant-derived natural products and combination therapy in liver cancer

“…the rhizome of the perennial herb turmeric in Zingiberaceae. In vitro and in vivo results showed that curcumin downregulated the expression of Bcl2-associated transcription factor (BCLAF1), inhibited the activation of PI3K/AKT/glycogen synthase kinase-3b (GSK-3b) pathway, and triggered mitochondria-mediated apoptosis in liver cancer (50). Sun et al reported that curcumin inhibited SMMC-7721 cell proliferation by induction of apoptosis via activating C/EBP homologous protein (CHOP) signaling pathway, reducing the expression of Bcl-2 and increasing cleaved caspase-3 and suppressed SMMC-7721 cell growth in xenograft tumor nude mice by activating endoplasmic reticulum (ER) stress pathway (51).…”

Antitumor from Several Plant Compounds Against Hepatocellular Carcinoma Cell Line Hep3B: Mini Systematic Review

“…Pengobatan garis sel hepatoma manusia, HepG2 dan SK-Hep-1, dengan berbagai konsentrasi kurkumin menunjukkan penghambatan proliferasi sel yang bergantung pada waktu dan konsentrasi, peningkatan apoptosis, penghentian siklus sel pada fase G0/G1, penurunan potensial membran mitokondria, dan penurunan level ekspresi PI3K, p-PI3K, AKT, p-AKT, GSK-3β, dan p-GSK-3β. Apoptosis mitokondria terlibat dalam aktivitas antikanker kurkumin melalui penargetan ekspresi BCLAF1 dalam lini sel HepG2 dan SK-Hep-1, dan mekanisme tersebut mungkin mengacu pada regulasi jalur pensinyalan PI3K/AKT/GSK-3β in vitro dan in vivo (Bai et al, 2022). Penelitian serupa tentang efek anti kanker dari kurkumin juga menunjukkan hal yang sama.…”