scholarly journals Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells

2019 ◽  
Vol 20 (9) ◽  
pp. 2069 ◽  
Author(s):  
Dmytro Starenki ◽  
Nadiya Sosonkina ◽  
Seung-Keun Hong ◽  
Ricardo V. Lloyd ◽  
Jong-In Park
Keyword(s):  
Cell Death ◽  
Thyroid Carcinoma ◽  
Thyroid Tumor ◽  
Anaplastic Thyroid Carcinoma ◽  
Mitochondrial Activity ◽  
Phase Arrest ◽  
M Phase ◽  
A Cell ◽  
Mitochondrial Hsp70

We previously reported that upregulation of mortalin (HSPA9/GRP75), the mitochondrial HSP70 chaperone, facilitates tumor cell proliferation and survival in human medullary thyroid carcinoma (MTC), proposing mortalin as a novel therapeutic target for MTC. In this report, we show that mortalin is also upregulated in other thyroid tumor types, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and anaplastic thyroid carcinoma (ATC), and that mortalin depletion can effectively induce growth arrest and cell death in human PTC (TPC-1), FTC (FTC133), and ATC (8505C and C643) cells in culture. Intriguingly, mortalin depletion induced varied effects on cell cycle arrest (G0/G1 phase arrest in TPC-1 and C643, G2/M phase arrest in 8505C, and mild G2/M phase arrest with increased sub-G0/G1 population in FTC133) and on the levels of TP53, E2F-1, p21CIP1, p27KIP1, and poly (ADP-ribose) polymerase cleavage in these cells, suggesting that thyroid tumor cells respond to mortalin depletion in a cell type-specific manner. In these cells, we also determined the efficacy of triphenyl-phosphonium-carboxy-proxyl (Mito-CP) because this mitochondria-targeted metabolism interfering agent exhibited similar tumor suppressive effects as mortalin depletion in MTC cells. Indeed, Mito-CP also induced robust caspase-dependent apoptosis in PTC and ATC cell lines in vitro, exhibiting IC50 lower than PLX4032 in 8505C cells and IC50 lower than vandetanib and cabozantinib in TPC-1 cells. Intriguingly, Mito-CP-induced cell death was partially rescued by mortalin overexpression, suggesting that Mito-CP may inactivate a mechanism that requires mortalin function. These findings support the significance of mortalin and mitochondrial activity in a broad spectrum of thyroid cancer.

Dioscin inhibits the growth of human osteosarcoma by inducing G2/M‐phase arrest, apoptosis, and GSDME‐dependent cell death in vitro and in vivo

2019 ◽  
Vol 235 (3) ◽  
pp. 2911-2924 ◽  
Author(s):  
Qiuyue Ding ◽  
Wenda Zhang ◽  
Cheng Cheng ◽  
Fengbo Mo ◽  
Lei Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Human Osteosarcoma ◽  
Phase Arrest ◽  
M Phase ◽  
Dependent Cell

Increased cell death in osteopontin-deficient cardiac fibroblasts occurs by a caspase-3-independent pathway

2004 ◽  
Vol 287 (4) ◽  
pp. H1730-H1739 ◽  
Author(s):  
Ron Zohar ◽  
Baoqian Zhu ◽  
Peter Liu ◽  
Jaro Sodek ◽  
C. A. McCulloch
Keyword(s):  
Cell Death ◽  
Caspase 3 ◽  
Cardiac Fibroblasts ◽  
Chromatin Condensation ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
Wild Type ◽  
Nuclear Fragmentation ◽  
A Cell

Reperfusion-induced oxidative injury to the myocardium promotes activation and proliferation of cardiac fibroblasts and repair by scar formation. Osteopontin (OPN) is a proinflammatory cytokine that is upregulated after reperfusion. To determine whether OPN enhances fibroblast survival after exposure to oxidants, cardiac fibroblasts from wild-type (WT) or OPN-null (OPN−/−) mice were treated in vitro with H2O2to model reperfusion injury. Within 1 h, membrane permeability to propidium iodide (PI) was increased from 5 to 60% in OPN−/−cells but was increased to only 20% in WT cells. In contrast, after 1–8 h of treatment with H2O2, the percent of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-stained cells was more than twofold higher in WT than OPN−/−cells. Electron microscopy of WT cells treated with H2O2showed chromatin condensation, nuclear fragmentation, and cytoplasmic and nuclear shrinkage, which are consistent with apoptosis. In contrast, H2O2-treated OPN−/−cardiac fibroblasts exhibited cell and nuclear swelling and membrane disruption that are indicative of cell necrosis. Treatment of OPN−/−and WT cells with a cell-permeable caspase-3 inhibitor reduced the percentage of TUNEL staining by more than fourfold in WT cells but decreased staining in OPN−/−cells by ∼30%. Although the percentage of PI-permeable WT cells was reduced threefold, the percent of PI-permeable OPN−/−cells was not altered. Restoration of OPN expression in OPN−/−fibroblasts reduced the percentage of PI-permeable cells but not TUNEL staining after H2O2treatment. Thus H2O2-induced cell death in OPN-deficient cardiac fibroblasts is mediated by a caspase-3-independent, necrotic pathway. We suggest that the increased expression of OPN in the myocardium after reperfusion may promote fibrosis by protecting cardiac fibroblasts from cell death.

scholarly journals PARP inhibitor olaparib increases the oncolytic activity of dl922-947 in in vitro and in vivo model of anaplastic thyroid carcinoma

2014 ◽  
Vol 9 (1) ◽  
pp. 78-92 ◽  
Author(s):  
Carmela Passaro ◽  
Massimiliano Volpe ◽  
Ginevra Botta ◽  
Eloise Scamardella ◽  
Giuseppe Perruolo ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Parp Inhibitor ◽  
Anaplastic Thyroid Carcinoma ◽  
In Vivo Model ◽  
Oncolytic Activity

scholarly journals In Vitro Identification and Characterization of CD133pos Cancer Stem-Like Cells in Anaplastic Thyroid Carcinoma Cell Lines

PLoS ONE ◽  
2008 ◽  
Vol 3 (10) ◽  
pp. e3544 ◽  
Author(s):  
Giovanni Zito ◽  
Pierina Richiusa ◽  
Alessandra Bommarito ◽  
Elvira Carissimi ◽  
Leonardo Russo ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Anaplastic Thyroid Carcinoma ◽  
Carcinoma Cell Lines ◽  
Identification And Characterization ◽  
Thyroid Carcinoma Cell

scholarly journals Survivin in relation to Bcl-2, Bax and in situ apoptotic cell death in anaplastic thyroid carcinoma

2011 ◽  
Vol 63 (4) ◽  
pp. 955-963
Author(s):  
Sonja Selemetjev ◽  
Dubravka Cvejic ◽  
Svetlana Savin ◽  
I. Paunovic ◽  
S. Tatic
Keyword(s):  
Cell Death ◽  
Thyroid Carcinoma ◽  
Apoptotic Cell ◽  
Anaplastic Thyroid Carcinoma ◽  
Apoptotic Cell Death ◽  
Staining Score ◽  
Human Malignancy ◽  
Apoptotic Pathways ◽  
Individual Scores

Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive human malignancy. It is known that disturbances in apoptotic pathways have a great impact on tumor progression and aggressiveness. In this study the apoptosisrelated molecules Bcl-2 (antiapoptotic), Bax (proapoptotic) and survivin (an inhibitor of apoptosis) were analyzed immunohistochemically in thirty archival cases of ATC. In situ apoptotic cell death was analyzed by the TUNEL method. Mean Bcl-2 staining score (calculated from individual scores from 0-3) was low compared to those for Bax and survivin (p<0.05). High expression of survivin was associated with high Bax expression, and was significantly segregated from high Bcl-2 expressing cases (p<0.05). Despite high Bax expression, apoptotic cell death was low in the investigated carcinomas. In addition, the mean apoptotic index in high survivin expressing carcinomas was significantly lower than in low survivin expressing carcinomas (p<0.05). It could be concluded that down-regulation of Bcl-2 is counterbalanced by up-regulation of survivin, which may overcome the effects of high Bax expression, and, at least partly, explain the low apoptosis rate and high biological aggressiveness of ATC.

Novel Thiadiazoline Spiro Quinoline Analogues Induced Cell death in MCF-7 cells via G2/M Phase Cell Cycle Arrest

2021 ◽  
Author(s):  
Selvaraj Shyamsivappan ◽  
Raju Vivek ◽  
Thangaraj Suresh ◽  
Adhigaman Kaviyarasu ◽  
Sundarasamy Amsaveni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Spectroscopic Studies ◽  
Phase Cell ◽  
Quinoline Derivatives ◽  
Cycle Arrest ◽  
M Phase ◽  
Mcf 7

Abstract A progression of novel thiadiazoline spiro quinoline derivatives were synthesized from potent thiadiazoline spiro quinoline derivatives . The synthesized compounds portrayed by different spectroscopic studies and single X-ray crystallographic studies. The compounds were assessed for in vitro anticancer properties towards MCF-7 and HeLa cells. The compounds showed superior inhibition action MCF-7 malignant growth cells. Amongst, the compound 4a showed significant inhibition activity, the cell death mechanism was evaluated by fluorescent staining, and flow cytometry, RT-PCR, and western blot analyses. The in vitro anticancer results revealed that the compound 4a induced apoptosis by inhibition of estrogen receptor alpha (ERα) and G2/M phase cell cycle arrest. The binding affinity of the compounds with ERα and pharmacokinetic properties were confirmed by molecular docking studies.

Casticin Induced Apoptosis in A375.S2 Human Melanoma Cells through the Inhibition of NF-κB and Mitochondria-Dependent Pathways In Vitro and Inhibited Human Melanoma Xenografts in a Mouse Model In Vivo

2016 ◽  
Vol 44 (03) ◽  
pp. 637-661 ◽  
Author(s):  
Yin-Wen Shiue ◽  
Chi-Cheng Lu ◽  
Yu-Ping Hsiao ◽  
Ching-Lung Liao ◽  
Jing-Pin Lin ◽  
...  
Keyword(s):  
Human Melanoma ◽  
Oxygen Species ◽  
Protein Levels ◽  
Phase Arrest ◽  
Viable Cells ◽  
M Phase ◽  
Induced Apoptosis ◽  
Western Blotting Assay

Casticin, a polymethoxyflavone occurring in natural plants, has been shown to have anticancer activities. In the present study, we aims to investigate the anti-skin cancer activity of casticin on melanoma cells in vitro and the antitumor effect of casticin on human melanoma xenografts in nu/nu mice in vivo. A flow cytometric assay was performed to detect expression of viable cells, cell cycles, reactive oxygen species production, levels of [Formula: see text] and caspase activity. A Western blotting assay and confocal laser microscope examination were performed to detect expression of protein levels. In the in vitro studies, we found that casticin induced morphological cell changes and DNA condensation and damage, decreased the total viable cells, and induced G2/M phase arrest. Casticin promoted reactive oxygen species (ROS) production, decreased the level of [Formula: see text], and promoted caspase-3 activities in A375.S2 cells. The induced G2/M phase arrest indicated by the Western blotting assay showed that casticin promoted the expression of p53, p21 and CHK-1 proteins and inhibited the protein levels of Cdc25c, CDK-1, Cyclin A and B. The casticin-induced apoptosis indicated that casticin promoted pro-apoptotic proteins but inhibited anti-apoptotic proteins. These findings also were confirmed by the fact that casticin promoted the release of AIF and Endo G from mitochondria to cytosol. An electrophoretic mobility shift assay (EMSA) assay showed that casticin inhibited the NF-[Formula: see text]B binding DNA and that these effects were time-dependent. In the in vivo studies, results from immuno-deficient nu/nu mice bearing the A375.S2 tumor xenograft indicated that casticin significantly suppressed tumor growth based on tumor size and weight decreases. Early G2/M arrest and mitochondria-dependent signaling contributed to the apoptotic A375.S2 cell demise induced by casticin. In in vivo experiments, A375.S2 also efficaciously suppressed tumor volume in a xenotransplantation model. Therefore, casticin might be a potential therapeutic agent for the treatment of skin cancer in the future.

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