Green tea-derived theabrownin induces cellular senescence and apoptosis of hepatocellular carcinoma through p53 signaling activation and bypassed JNK signaling suppression

Abstract

Background Theabrownin (TB) is a bioactive component of tea and has been reported to exert effects against many human cancers, but its efficacy and mechanism on hepatocellular carcinoma (HCC) with different p53 genotypes remains unclarified. Methods MTT assay, DAPI staining, flow cytometry and SA-β-gal staining were applied to evaluate the effects of TB on HCC cells. Quantitative real time PCR (qPCR) and Western blot (WB) were conducted to explore the molecular mechanism of TB. A xenograft model of zebrafish was established to evaluate the anti-tumor effect of TB. Results MTT assays showed that TB significantly inhibited the proliferation of SK-Hep-1, HepG2, and Huh7 cells in a dose-dependent manner, of which SK-Hep-1 was the most sensitive one with the lowest IC50 values. The animal data showed that TB remarkably suppressed SK-Hep-1 tumor growth in xenograft model of zebrafish. The cellular data showed TB's pro-apoptotic and pro-senescent effect on SK-Hep-1 cells. The molecular results revealed the mechanism of TB that p53 signaling pathway (p-ATM, p-ATR, γ-H2AX, p-Chk2, and p-p53) was activated with up-regulation of downstream senescent genes (P16, P21, IL-6 and IL-8) as well as apoptotic genes (Bim, Bax and PUMA) and proteins (Bax, c-Casp9 and c-PARP). The p53-mediated mechanism was verified by using p53-siRNA. Moreover, by using JNK-siRNA, we found JNK as a bypass regulator in TB's mechanism. Conclusions To sum up, TB exerted tumor-inhibitory, pro-senescent and pro-apoptotic effects on SK-Hep-1 cells through ATM-Chk2-p53 signaling axis in accompany with JNK bypass regulation. This is the first report on the pro-senescent effect and multi-target (p53 and JNK) mechanism of TB on HCC cells, providing new insights into the underlying mechanisms of TB's anti-HCC efficacy.

Theabrownin Alleviates Colorectal Tumorigenesis in Murine AOM/DSS Model via PI3K/Akt/mTOR Pathway Suppression and Gut Microbiota Modulation

“…However, regardless of these different processes, consistent tumor suppressive effects of TB were found among different research utilizing TB from different sources. TB was found to have tumor suppressive effects against multiple cancers, including non-small-cell lung cancer, osteosarcoma, hepatocellular carcinoma, gliomas, and melanoma, through modulating oncogenic pathways, PI3K/Akt, p53/JNK, and NF-κB pathway [ 15 , 16 , 17 , 18 , 19 , 20 ]. In CRC, TB was recently reported to inhibit cell growth and promote apoptosis in human CRC cells, HT29 [ 15 ].…”

Human microbiomes in cancer development and therapy

“…Telomerase activation is observed in over 90% of HCC patients and is closely related to HCC. 177 C‐terminally truncated middle surface protein of hepatitis B virus (MHBst) and wild‐type/truncated HBx proteins activate the transcripts promoter of TERT in HBV‐associated HCC. 178 Many signaling pathways were activated in HCC such as Wnt/β‐Catenin, cell cycle, oxidative stress metabolic pathway, Ras/ MAPK, and so on.…”

“…On the other hand, HBx viral protein can also promote carcinogenesis by maintaining centrosome integrity though Crm 1 and affecting mitosis checkpoint. Telomerase activation is observed in over 90% of HCC patients and is closely related to HCC 177 . C‐terminally truncated middle surface protein of hepatitis B virus (MHBst) and wild‐type/truncated HBx proteins activate the transcripts promoter of TERT in HBV‐associated HCC 178 .…”

Hsp Inhibitor is Affective Against Adenocarcinomic Human Alveolar Basal Epithelial Cells Through Modulating ERK/MAPK Signaling Pathway

“…Pyrazole moiety used as dual HSP70 and HSP90 inhibitor functional group as identified in our previous work and the inhibitor was patented. [24,27] This study focuses on changes in the MAPK signaling at the molecular level in the presence of PP inhibitors. Some of the clinical drugs resist NSCLC patients over time in the treatment.…”

“…Preliminary results indicated the compounds potential effectiveness. Pyrazole moiety used as dual HSP70 and HSP90 inhibitor functional group as identified in our previous work and the inhibitor was patented [24,27] …”