Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the MAPK signaling pathway

Abstract

Fisetin (3,3',4',7-tetrahydroxyflavone), a dietary flavonoid compound, is currently being investigated for its anticancer effect in various cancer models, including lung cancer. Recent studies show that fisetin induces cell growth inhibition and apoptosis in the human non-small cell lung cancer line NCI-H460. In this study, we investigated whether fisetin can induce endoplasmic reticulum (ER) stress-mediated apoptosis in NCI-H460 cells. Fisetin induced mitochondrial reactive oxygen species (ROS) and characteristic signs of ER stress: ER staining; mitochondrial Ca(2+) overload; expression of ER stress-related proteins; glucose-regulated protein (GRP)-78, phosphorylation of protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) and phosphorylation of eukaryotic initiation factor-2 α subunit; cleavage of activating transcription factor-6; phosphorylation of inositol-requiring kinase-1 and splicing of X-box transcription factor-1; induction of C/EBP homologous protein and cleaved caspase-12. siRNA-mediated knockdown of CHOP and ATF-6 attenuated fisetin-induced apoptotic cell death. In addition, fisetin induced phosphorylation of ERK, JNK, and p38 MAPK. Moreover, silencing of the MAPK signaling pathway prevented apoptotic cell death. In summary, our results indicate that, in NCI-H460 cells, fisetin induces apoptosis and ER stress that is mediated by induction of the MAPK signaling pathway.

Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells

“…CHOP is the best-characterized factor in the transition from ERS to cell apoptosis [50]. CHOP-knockdown cells are resistant to cell apoptosis that is usually induced by ERS [16], that can lead to various processes, including autophagy and apoptosis, which function as the regulators of cell survival and death [19, 20]. ERS can also activate the unfolded protein response, which reports have earmarked due to their role in chemotherapeutic resistance or antitumor therapy based on the stimuli and cell context [51].…”

“…Recently, endoplasmic reticulum stress (ERS) has been highlighted due to its extensive involvement in the development and progression of LC [16, 17]. The endoplasmic reticulum (ER) is a common organelle feature of many cells among various species.…”

“…The endoplasmic reticulum (ER) is a common organelle feature of many cells among various species. The ER offers a region for protein folding and modification and is responsible for the storage of intracellular stores of calcium (Ca 2+ ) [16]. Pathological and physiological stimuli, such as DNA damage, hypoxia, oxidative stress, and nutrition, can disturb the normal ER functions, which may consequently lead to misfolded or unfolded ER proteins, and in turn cause an increase in mitochondrial Ca 2+ , thus inducing ERS [18].…”

Fisetin Protects PC12 Cells from Tunicamycin-Mediated Cell Death via Reactive Oxygen Species Scavenging and Modulation of Nrf2-Driven Gene Expression, SIRT1 and MAPK Signaling in PC12 Cells

“…It was reported that fisetin at low concentrations provides neuroprotection in several models [25,26,27,28,29], while at high concentrations it induces reactive oxygen species (ROS) production, ER stress and cell death in some tumor cells [30,31,32]. We found that treatment of PC12 cells with fisetin (up to 40 µM) alone for 16 h did not alter cell viability (Figure 1b).…”

Identifying reproducible cancer-associated highly expressed genes with important functional significances using multiple datasets

“…3a). Besides, the DNA replication pathway19 commonly found by PD and SAM, the other 13 significant pathways are mainly associated with lung cancer, including pentose phosphate pathway20, oxidative phosphorylation921, cysteine and methionine metabolism22, glutathione metabolism101112, biosynthesis of amino acids23, ribosome24, proteasome13, protein processing in endoplasmic reticulum2526, phagosome27 and TNF signaling pathway28. These conservative pathways included many DE genes highly expressed in both cancer and normal tissues, which tended to be missed by SAM.…”