Abstract
Polyphyllin has been reported to exhibit anticancer effects against various types of cancer via the proapoptotic signaling pathway. The aim of the present study was to investigate the role of the endoplasmic reticulum stress and death receptor signaling pathways in PPI-induced apoptosis of human hepatocellular carcinoma HepG2 cells. Analysis demonstrated that PPI could significantly inhibit the proliferation and induce apoptosis of HepG2 cells in a dose- and time-dependent manner. Investigation into the molecular mechanism of PPI indicated that PPI notably mediated ER stress activation via IRE-1 overexpression and activation of the caspase-12 to protect HepG2 cells against apoptosis. In addition, PPI markedly induced the expression of death receptors signaling pathways-associated factors, including tumor necrosis factor (TNF) receptor 1/TNF-α and FAS/FASL. Additionally, suppression of the death receptor signaling pathways with a caspase-8 inhibitor, Z-IETD-FMK, revealed an increase in the death rate and apoptotic rate of HepG2 cells. Collectively, the findings of the present study suggested that the ER stress and death receptor signaling pathways were associated with PPI-induced HepG2 cell apoptosis; however, endoplasmic reticulum stress may serve a protective role in this process. The combination of PPI and Z-IETD-FMK may activate necroptosis, which enhances apoptosis. Therefore, the results of the present study may improve understanding regarding the roles of signaling pathways in PPI regulated apoptosis and contribute to the development of novel therapies for the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC), the most common type of malignancy of the liver, has been reported as the fifth leading cause of cancer and the third leading cause of cancer associated death worldwide [1]
To determine the effects of Polyphyllin I (PPI) on cell viability, HepG2 cells were treated with various concentrations of PPI for 6, 12, and 24 h and the inhibition of cell proliferation was detected via a Cell Counting Kit-8 (CCK-8) assay
Previous studies have demonstrated that traditional Chinese medicines, including PPI, may be considered as potential therapeutic agents for the treatment of human cancers [29]; the molecular mechanisms underlying the anticancer properties of PPI, towards HCC, require further investigation
Summary
Hepatocellular carcinoma (HCC), the most common type of malignancy of the liver, has been reported as the fifth leading cause of cancer and the third leading cause of cancer associated death worldwide [1]. Polyphyllin I (PPI), a steroidal saponin extracted from the rhizoma of Paris polyphyllin (Figure 1(a)), has been reported to inhibit the proliferation of various types of cancer, including lung cancer [4], HCC [5], ovarian cancer [6], human osteosarcoma [7], and others. The foremost reported antitumor mechanism underlying the action of PPI was associated with the induction of apoptosis [5]. PPI induced cell apoptosis via activating the caspase cascade, inducing mitochondrial fragmentation [8], and modulating the βcatenin signaling pathway [9]. Extensive investigation of the molecular pathways underlying PPI-induced
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call