Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Abstract

As a traditional herbal medicine, the fruits of Psoralea corylifolia L. (Fructus Psoraleae (FP)) have been widely used for the treatment of various skin diseases for hundred years. Recently, the emerging FPinduced toxic effects, especially hepatotoxicity, in clinic are getting the public's attention. However, its exact toxic components and mechanisms underlying remain unclear. Bavachin, one of flavonoids in FP, has been documented as a hepatotoxic substance, and the present study aimed to determine the toxicity caused by bavachin and the possible toxic mechanisms involved using human hepatocellular carcinoma (HepG2) cells. Our results showed that bavachin could significantly inhibited cell proliferation and trigger the endoplasmic reticulum (ER) stress in a dose dependent manner. Downregulating ER stress using tauroursodeoxycholic acid (TUDCA) obvious attenuated bavachin-triggerd cell apoptosis. Then, small interfering RNA (siRNA) knock-down of Mitofusion2 (Mfn2) resulted in a remarkable aggravation of ER stress through the inhibition of the phosphorylation of protein kinase B (Akt). Additionally, suppression of reactive oxygen species (ROS) by ROS Scavenger (N-acetyl-l-cystein (NAC)) also reduced bavachin-induced ER stress. Taken together, our study demonstrated that bavachin-induced ER stress caused cell apoptosis by Mfn2-Akt pathway, and that ROS may participate upstream in this mechanism. Here, we not only provide a new understanding of ROS/ Mfn2/Akt pathway in bavachin-induced cytotoxicity via the ER stress, but also identify a new specific intervention to prevent FP-induced hepatotoxicity in the future.

Natural Products Targeting ER Stress, and the Functional Link to Mitochondria

“…The results showed how the HepG2 cells exhibited a gradual decrease in the Mfn2 protein levels and how small interfering RNA (siRNA) knock-down of Mfn2 resulted in a remarkable aggravation of ER stress through the inhibition of protein kinase B (Akt) phosphorylation. Along with these observations, results also displayed how the suppression of ROS by ROS scavengers reduced bavachin-induced ER stress [31].…”

Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway

“…This finding is consistent with those from previous studies [51,58]. For example, in HepG2 cells, increased Mfn2 expression attenuates ER stress, sustaining cellular viability and mitochondrial function [59]. In addition, in Parkinson's disease, Mfn2related ER stress also modulates neurodegeneration in a manner dependent on the PINK1/Parkin pathway [60,61].…”

Role of Mitofusins and Mitophagy in Life or Death Decisions

“…However, apoptosis is generally accompanied by mitochondrial fragmentation and, indeed, MFN2 was shown to be phosphorylated and proteasomally degraded upon genotoxic stress, which also induced apoptosis (Leboucher et al, 2012). Besides, Mfn2 depletion in murine liver was shown to aggravate apoptosis provoked by bavachin, a flavonoid causing ER-stress, and Mfn2 depletion in the hippocampus led to neuronal death (Yang et al, 2018;Han et al, 2020). Other than leading to mitofusins degradation, apoptosis might inactivate the fusogenic capacity of mitofusins, perhaps directly mediated by activated BAX/BAK oligomers (Karbowski et al, 2006).…”