Ethyl Acetate Extract of Scindapsus cf. hederaceus Exerts the Inhibitory Bioactivity on Human Non-Small Cell Lung Cancer Cells through Modulating ER Stress

Abstract

Unfolded protein response (UPR) is a cytoprotective mechanism that alleviates the protein-folding burden in eukaryotic organisms. Moderate activation of UPR is required for maintaining endoplasmic reticulum (ER) homeostasis and profoundly contributes to tumorigenesis. Defects in UPR signaling are implicated in the attenuation of various malignant phenotypes including cell proliferation, migration, and invasion, as well as angiogenesis. This suggests UPR as a promising target in cancer therapy. The pharmacological effects of the plant Scindapsus cf. hederaceus on human cancer cell lines is not understood. In this study, we identified an ethyl acetate extract from Scindapsus cf. hederaceus (SH-EAE), which markedly altered the protein expression of UPR-related genes in human non-small cell lung cancer (NSCLC) cells. Treatment with the SH-EAE led to the dose-dependent suppression of colony forming ability of both H1299 and H460 cells, but not markedly in normal bronchial epithelial BEAS-2B cells. SH-EAE treatment also attenuated the migration and invasion ability of H1299 and H460 cells. Moreover, SH-EAE strikingly suppressed the protein expression of two ER stress sensors, including inositol requiring enzyme-1α (IRE-1α) and protein kinase R-like ER kinase (PERK), and antagonized the induction of C/EBP homologous protein (CHOP) expression by thapsigargin, an ER stress inducer. SH-EAE induced the formation of massive vacuoles which are probably derived from ER. Importantly, SH-EAE impaired the formation of intersegmental vessels (ISV) in zebrafish larvae, an index of angiogenesis, but had no apparent effect on the rate of larval development. Together, our findings demonstrate, for the first time, that the ability of SH-EAE specifically targets the two sensors of UPR, with significant anti-proliferation and anti-migration activities as a crude extract in human NSCLC cells. Our finding also indicates potential applications of SH-EAE in preventing UPR activation in response to Tg-induced ER stress. We suggest that SH-EAE attenuates UPR adaptive pathways for rendering the NSCLC cells intolerant to ER stress.

Role of Endoplasmic Reticulum Stress in the Anticancer Activity of Natural Compounds

“…About this, it has recently been shown that an ethyl acetate extract from Scindapsus cf. hederaceus (SH-EAE), by decreasing the expression of PERK and IRE1α, exerts anti-proliferative and anti-migratory activities in human lung cancer cells; moreover experiments in zebrafish demonstrated that a decreased expression of PERK and IRE1α in SH-EAE-treated lung cancer cells is accompanied by the reduction of vessels development, suggesting an antiangiogenic effect [ 131 ]. The expression of ER stress sensor BiP may be enhanced in metastatic cells, and BiP could represent an advantageous therapeutic target [ 132 ].…”

Antiangiogenesis Efficacy of Ethanol Extract from Amomum tsaoko in Ovarian Cancer through Inducing ER Stress to Suppress p‐STAT3/NF‐kB/IL‐6 and VEGF Loop

“…ER stress is found to be a new pathway leading to apoptosis [52]. In recent studies, ER stress is considered to be associated with angiogenesis [53,54], but the mechanism is not well understood. In our previous studies, drug-induced ER stress inhibits the activation of p-STAT3 [1,12].…”

Induction of mitochondria-mediated apoptosis and suppression of tumor growth in zebrafish xenograft model by cyclic dipeptides identified from Exiguobacterium acetylicum

“…A possible explanation www.nature.com/scientificreports/ for the low and high peptide concentrations required for significant growth inhibition of various cancer cells described above is owing to several factors including the possibility of DKPs binding to serum proteins in the culture medium, and drug efflux by P-glycoprotein, or the lack of sufficient absorption of peptides into the cells 25 . A key mechanism involved in the action of many anticancer drugs is the activation of extrinsic and intrinsic apoptotic pathways [31][32][33][34] . The crucial element in the intrinsic apoptotic pathway is the efflux of Cytc from mitochondria to the cytosol.…”