Curcumin Activates ROS Signaling to Promote Pyroptosis in Hepatocellular Carcinoma HepG2 Cells

Abstract

Background/Aim: Curcumin is a polyphenol that exerts a variety of pharmacological activities and plays an anti-cancer role in many cancer cells. It was recently reported that gasdermin E (GSDME) is involved in the progression of pyroptosis. Materials and Methods: HepG2 cells were treated with various concentrations of curcumin and cell viability was examined using MTT assay, apoptosis was analysed using flow cytometry, reactive oxygen species (ROS) levels using dihydroethidium, LDH release using an LDH cytotoxicity assay, and protein expression using western blot. Results: Curcumin increased the expression of the GSDME N-terminus and proteins involved in pyrolysis, promoted HspG2 cell pyrolysis and increased intracellular ROS levels. Moreover, inhibition of the production of intracellular ROS with nacetylcysteine (NAC) improved the degree of apoptosis and pyrolysis induced by curcumin. Conclusion: Curcumin induces HspG2 cell death by increasing apoptosis and pyroptosis, and ROS play a key role in this process. This study improves our understanding of the potential anti-cancer properties of curcumin in liver cancer. Curcumin[1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6heptadiene-3,5-dione (diferuloy l methane)] is a type of polyphenol extracted from the rhizomes of ginger plants, such as turmeric and zedoary (1), which has been shown to display various pharmacological activities, including antiinflammatory (2), antioxidant (3), hypolipidemic (4), antitumor (5), and immune regulatory (6). Previous studies have also demonstrated that curcumin exerts anti-cancer effects in many types of cancer cells, including stomach (7), colon (8), lung (9), liver (10) and breast (11). In addition, it has been reported that curcumin can affect the cellular redox balance, resulting in increased cellular reactive oxygen species (ROS) production (12). Excessive ROS can directly or indirectly affect the regulation of anti-or pro-apoptotic proteins by Bcl-2 family members, leading to cellular apoptosis (13). Moreover, ROS accumulation has been shown to induce cellular apoptosis, necroptosis, endoplasmic reticulum stress, and autophagy in various cancer cells (14). Therefore, curcumin may also affect cell death in liver cancer cells.Pyroptosis is a recently discovered type of programmed cell death that depends on the activation of the inflammationrelated caspases 1, 4, 5, and 11, as well as apoptosis-related caspase-3 (15). The morphology of cells undergoing pyroptosis differs from that in apoptosis or necrosis, and is characterized by cell swelling, membrane breakage, pore formation, and osmotic lysis (16). It was recently reported that gasdermin E (GSDME) is involved in the progression of pyroptosis (17). In particular, activated caspase-3 was found to cleave GSDME between the N-terminus (GSMDE-N) and C-terminus under certain apoptotic stimuli, thus relieving the self-inhibition of the C-terminus and releasing the active GSDME-N-terminus as well as the pore-forming domain (PFD). Consequently, nonselective pores are formed in the cell membra...

N-acetyl-L-tryptophan attenuates hepatic ischemia-reperfusion injury via regulating TLR4/NLRP3 signaling pathway in rats

“…Interleukin-1β (IL-1β), an important mediator of inflammatory response after ischemia-reperfusion, could induce the synthesis of other inflammatory factors, chemokines and adhesion molecules, etc. The cascade magnification reaction, which causes pathological inflammatory response, is an important “executor” of cell pyroptosis-induced cell inflammatory death ( Liang et al, 2021 ).…”

Curcumin activates NLRC4, AIM2, and IFI16 inflammasomes and induces pyroptosis by up-regulated ISG3 transcript factor in acute myeloid leukemia cell lines

“…Liping Chen et al 21 found that the curcumin derivative exhibited good anti-tumor activity both in vitro and in vivo via the switch of apoptosis-to-pyroptosis. Wan-Feng Liang 10 found that curcumin activates ROS signaling to promote pyroptosis in hepatocellular carcinoma HepG2 cells. In our studies, we found that heterologously overexpressing GSDMD enhanced sensitivity of K562 cell to curcumin, and inhibition of GSDMD with shRNA in U937 cells enhance curcumin anti-leukemia effect, indicating that the sensitivity of leukemia cells to curcumin is clearly related to pyroptosis.…”

“… 5 , 7–9 Recent studies have found that curcumin can induce pyroptosis of solid tumor cells. 10 , 11 However, it is not clear whether pyroptosis is involved in the anti-leukemia effect of curcumin.…”

Curcumin improves the function of umbilical vein endothelial cells by inhibiting H2O2‑induced pyroptosis

“…1A ), a polyphenolic compound, is the principal curcuminoid derived from the rhizomes of turmeric ( 12 ); it is able inhibit lipopolysaccharide-induced NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, thereby inhibiting the activation of IL-1β and caspase-1 ( 13 , 14 ). In addition, curcumin also exhibits antioxidant and anti-tumor properties ( 15 – 17 ).…”