scholarly journals Sea Hare Hydrolysate-Induced Reduction of Human Non-Small Cell Lung Cancer Cell Growth through Regulation of Macrophage Polarization and Non-Apoptotic Regulated Cell Death Pathways

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 726 ◽  
Author(s):  
Marie Merci Nyiramana ◽  
Soo Buem Cho ◽  
Eun-Jin Kim ◽  
Min Jun Kim ◽  
Ji Hyeon Ryu ◽  
...  
Keyword(s):  
Cell Death ◽  
Macrophage Activation ◽  
Macrophage Polarization ◽  
A549 Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Sea Hare ◽  
Cell Death Pathways ◽  
Anticancer Effects ◽  
Regulated Cell Death

Sea hare-derived compounds induce macrophage activation and reduce asthmatic parameters in mouse models of allergic asthma. These findings led us to study the role of sea hare hydrolysates (SHH) in cancer pathophysiology. SHH treatment-induced M1 macrophage activation in RAW264.7 cells, peritoneal macrophages, and THP-1 cells, as did lipopolysaccharide (LPS) (+ INF-γ), whereas SHH reduced interleukin (IL)-4 (+IL-13)-induced M2 macrophage polarization. In addition, SHH treatment inhibited the actions of M1 and M2 macrophages, which have anticancer and pro-cancer effects, respectively, in non-small cell lung cancer cells (A549 and HCC-366) and tumor-associated macrophages (TAMs). Furthermore, SHH induced G2/M phase arrest and cell death in A549 cells. SHH also downregulated STAT3 activation in macrophages and A549 cells, and the down-regulation was recovered by colivelin, a STAT3 activator. SHH-induced reduction of M2 polarization and tumor growth was blocked by colivelin treatment. SHH-induced cell death did not occur in the manner of apoptotic signaling pathways, while the death pattern was mediated through pyroptosis/necroptosis, which causes membrane rupture, formation of vacuoles and bleb, activation of caspase-1, and secretion of IL-1β in SHH-treated A549 cells. However, a combination of SHH and colivelin blocked caspase-1 activation. Z-YVAD-FMK and necrostatin-1, pyrotosis and necroptosis inhibitors, attenuated SHH’s effect on the cell viability of A549 cells. Taken together, SHH showed anticancer effects through a cytotoxic effect on A549 cells and a regulatory effect on macrophages in A549 cells. In addition, the SHH-induced anticancer effects were mediated by non-apoptotic regulated cell death pathways under STAT3 inhibition. These results suggest that SHH may be offered as a potential remedy for cancer immunotherapy.

scholarly journals Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes

2020 ◽  
Author(s):  
Christina M. Bebber ◽  
Emily S. Thomas ◽  
Zhiyi Chen ◽  
Jenny Stroh ◽  
Ariadne Androulidaki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Death Pathways ◽  
Regulated Cell Death ◽  
Regulated Necrosis ◽  
Treatment Naïve

AbstractBi-allelic loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests strong selective pressure to inactivate regulated cell death pathways prior to therapy. Yet, which regulated cell death pathways remain available in treatment-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability, we identify non-neuroendocrine (NE) and NE SCLC subtypes to segregate by their response to ferroptosis, a recently described iron-dependent type of regulated necrosis. While we identify that in treatment-naïve SCLC extrinsic apoptosis and necroptosis are incapacitated, we find non-NE SCLC to be exquisitely sensitive to ferroptosis induced through pharmacological and genetic means. Mechanistically, non-NE SCLC as opposed to NE SCLC presents with an oxygenated lipidome priming non-NE SCLC for ferroptosis. ASCL1+ NE SCLC, in turn, is resistant to ferroptosis but acquires selective addiction to the thioredoxin (TRX) anti-oxidant pathway. Importantly, co-cultures mimicking non-NE/NE intratumoral heterogeneity selectively deplete non-NE populations upon induction of ferroptosis while eliminating NE cell populations only upon TRX pathway. As a consequence, combined induction of ferroptosis and inhibition of the TRX pathway broadly kills established non-NE and NE tumors in xenografts and genetically engineered mouse models of SCLC. Moreover, patient-derived treatment-naïve and refractory NE SCLC models are selectively killed via this regime. In SCLC, combined low expression of GPX4 and TRX reductase 1 (TXNRD1) identifies a patient subset with drastically improved overall survival. These data identify ferroptosis as an SCLC subtype-specific vulnerability and suggest repurposing ferroptosis induction with TRX pathway inhibition to specifically address intratumoral NE/non-NE heterogeneity in SCLC.One Sentence SummaryThe SCLC non-neuroendocrine subtype is sensitive to ferroptosis

scholarly journals Lidocaine Inhibited Migration of Non-Small-Cell Lung Cancer A549 Cells via the CXCR4 Regulation

2021 ◽  
Author(s):  
Baichun Xing ◽  
Linlin Yang ◽  
Yanan Cui
Keyword(s):  
Wound Healing ◽  
Cell Death ◽  
Cell Viability ◽  
Plasma Concentrations ◽  
A549 Cells ◽  
Small Cell ◽  
Filamentous Actin ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Intracellular Ca

Abstract BackgroundLidocaineis a local anestheticthat wildly used in surgical treatment and postoperative medical care for lung cancers.We hypothesized thatlidocaine at clinical plasma concentrationcan inhibit CXCL12/CXCR4 axis regulated cytoskeletal remodeling thereby decrease migration ofNon-small-cell lung cancers (NSLC) cells. MethodsWe determined the effect of lidocaine at clinical plasma concentration on CXCL12-induced cell viability, apoptosis, cell death, monolayer cell wound healing rate, individual cell migration indicators, expression of CXCR4, CD44, and ICAM-1, intracellular Ca2+level, and filamentous actin level alteration of NSLC cells A549 and CXCR4-knocked down A549 cells using CCK-8, Bcl-2 ELISA, Cell death ELISA, wound healing assay, chemotaxis assay, western blotting, QPCR, Fura-2-based intracellular Ca2+assay, and Fluorescein Phalloidin staining respectively.ResultsLidocaine did not affect cell viability, apoptosis, and cell death but inhibited CXCL12-induced migration,intracellular Ca2+ releasing, and filamentous actin increase. Lidocaine decreased expression of CXCR4, increased CD44, but had no effect on ICAM-1. CXCL12induced the increase of CD44 and ICAM-1 but did not affect CD44 in the presence of lidocaine.The knockdown of CXCR4 eliminated all the effects of lidocaine.ConclusionLidocaine at clinical plasma concentrations inhibited CXCL12-induced CXCR4 activation, thereby reduced the intracellular Ca2+-dependent cytoskeleton remodeling, resulting in slower migration of A549 cells.

scholarly journals Expression of cyclin B1 after induction of senescence and cell death in non-small cell lung carcinoma A549 cells

2012 ◽  
Vol 50 (1) ◽  
pp. 58-67 ◽  
Author(s):  
Agnieszka Żuryń ◽  
Maciej Gagat ◽  
Aleksandra Antonina Grzanka ◽  
Lidia Gackowska ◽  
Alina Grzanka
Keyword(s):  
Cell Death ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
A549 Cells ◽  
Cyclin B1 ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

scholarly journals A novel PPARɣ ligand, PPZ023, overcomes radioresistance via ER stress and cell death in human non-small-cell lung cancer cells

2020 ◽  
Vol 52 (10) ◽  
pp. 1730-1743
Author(s):  
Tae Woo Kim ◽  
Da-Won Hong ◽  
Chang-Mo Kang ◽  
Sung Hee Hong
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Er Stress ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Caspase 3 ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cytochrome C Release ◽  
Anticancer Effects

Abstract Peroxisome proliferator-activated receptor gamma (PPARɣ) agonists exert powerful anticancer effects by suppressing tumor growth. In this study, we developed PPZ023 (1-(2-(ethylthio)benzyl)-4-(2-methoxyphenyl)piperazine), a novel PPAR ligand candidate, and investigated the underlying signaling pathways in both non-small-cell lung cancer (NSCLC) and radio-resistant NSCLC cells. To identify whether PPZ023 has anticancer effects in NSCLC and radioresistant NSCLC cells, we performed WST-1, LDH, Western blot, and caspase-3 and -9 activity assays. Furthermore, we isolated exosomes from PPZ023-treated NSCLC cells and studied cell death signaling. PPZ023 reduces cell viability and increases LDH cytotoxicity and caspase-3 activity in NSCLC cells. PPZ023 induces cell death by generating reactive oxygen species (ROS) and triggering mitochondrial cytochrome c release. PPZ023 treatment causes cell death via the PERK–eIF2α–CHOP axis in both NSCLC cell lysates and exosomes, and PERK and CHOP knockdown significantly blocks ER stress-mediated apoptosis by reducing cleaved caspase-3. Interestingly, diphenyleneiodonium (DPI, a Nox inhibitor) inhibits PPZ023-induced cell death via ER stress, and PPARɣ knockdown inhibits PPZ023-induced ROS, ER stress, and cell death. Moreover, PPZ023, in combination with radiation, causes synergic cell death via exosomal ER stress in radioresistant NSCLC cells, indicating that PPZ023/radiation overcomes radioresistance. Taken together, our results suggest that PPZ023 is a powerful anticancer reagent for overcoming radioresistance.

scholarly journals Proteasome Inhibitors Diminish c-Met Expression and Induce Cell Death in Non-Small Cell Lung Cancer Cells

2020 ◽  
Vol 28 (5) ◽  
pp. 497-507
Author(s):  
Yanhui Li ◽  
Su Dong ◽  
Arya Tamaskar ◽  
Heather Wang ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Viability ◽  
Small Cell Lung Cancer ◽  
Proteasome Inhibitors ◽  
A549 Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Induce Cell Death ◽  
H460 Cells

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for 85% of all lung carcinomas. The hepatocyte growth factor receptor (c-Met) has been considered as a potential therapeutic target for NSCLC. Proteasome inhibition induces cell apoptosis and has been used as a novel therapeutic approach for treating diseases including NSCLC; however, the effects of different proteasome inhibitors on NSCLC have not been fully investigated. The aim of this study is to determine a precise strategy for treating NSCLC by targeting c-Met using different proteasome inhibitors. Three proteasome inhibitors, bortezomib, MG132, and ONX 0914, were used in this study. Bortezomib (50 nM) significantly reduced c-Met levels and cell viability in H1299 and H441 cells, while similar effects were observed in H460 and A549 cells when a higher concentration (100 nM) was used. Bortezomib decreased c-Met gene expression in H1299 and H441 cells, but it had no effect in A549 and H460 cells. MG-132 at a low concentration (0.5 M) diminished c-Met levels in H441 cells, while neither a low nor a high concentration (20 M) altered c-Met levels in A549 and H460 cells. A higher concentration of MG-132 (5 M) was required for decreasing c-Met levels in H1299 cells. Furthermore, MG-132 induced cell death in all four cell types. Among all the four cell lines, H441 cells expressed higher levels of c-Met and appeared to be the most susceptible to MG-132. MG-132 decreased c-Met mRNA levels in both H1299 and H441 cells. ONX 0914 reduced c-Met levels in H460, H1299, and H441 cells but not in A549 cells. c-Met levels were decreased the most in H441 cells treated with ONX 0914. ONX 0914 did not alter cell viability in H441; however, it did induce cell death among H460, A549, and H1299 cells. This study reveals that different proteasome inhibitors produce varied inhibitory effects in NSCLS cell lines.

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