Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling

Liu, Yu Peng; Yang, Chang-Hao; Huang, Ming Shyan; Yeh, Chi Tai; Wu, Alexander T.H.; Lee, Yu Cheng; Lai, Tsung‐Ching; Lee, Chien Hsin; Hsiao, Ya Wen; Lu, Jean; Shen, Chia‐Ning; Lu, Pei Jung; Hsiao, Michael

doi:10.1158/0008-5472.can-12-1733

Cited by 189 publications

(159 citation statements)

References 46 publications

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“…Treatment of DAPT plus t-AUCB can induce significant cell apoptosis and promote caspase-3 activity, which is essential in the apoptosis process. DAPT is widely used as a tool to block the Notch signaling pathway in studies of cancer therapy and can hence override chemoresistance by inhibiting the expression of Notch1 [23] . Thus, we herein detected the levels of Notch1 intracellular domain (NICD1) and the active region of the Notch1 receptor of cells under different experimental treatments by western blot.…”

Section: Discussionmentioning

confidence: 99%

γ-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway

Wang

2014

Acta Pharmacol Sin

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Aim: -cyclohexyloxy]-benzoic acid (t-AUCB) is a soluble epoxide hydrolase inhibitor that suppresses glioblastoma cell growth in vitro. The aim of this study was to examine whether the γ-secretase inhibitor N- [N-(3,5-difluorophenacetyl)-lalanyl]-S-phenylglycine t-butyl ester (DAPT) could sensitize glioma cells to t-AUCB-induced apoptosis. Methods: Both U251 and U87 human glioblastoma cell lines were tested. Cell growth was assessed using the cell counting kit-8. Cell apoptosis was detected with caspase-3 activity assay kits and flow cytometry. The protein levels in the p38 MAPK/MAPKAPK2/Hsp27 pathway in the cells were analyzed using Western blots. Results: Pretreatment with DAPT (2 μmol/L) substantially potentiated the growth inhibition caused by t-AUCB (200 μmol/L) in U251 and U87 cells. Furthermore, pretreatment with DAPT markedly increased t-AUCB-induced apoptosis of U251 and U87 cells. T-AUCB alone did not significant affect caspase-3 activity in the cells, but t-AUCB plus DAPT pretreatment caused significant increase of caspase-3 activity. Furthermore, pretreatment with DAPT completely blocked t-AUCB-induced phosphorylation of p38 MAPK, MAPKAPK2 and Hsp27 in the cells. Conclusion: The γ-secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway, suggesting that the combination of t-AUCB and DAPT may be a potentially effective strategy for the treatment of glioblastoma.

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Section: Discussionmentioning

confidence: 99%

γ-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway

Wang

2014

Acta Pharmacol Sin

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“…Therefore, it is possible that there are no DTPs present in the initial population of PC9 cells. If this is the case, then we propose that the DTP phenotype must be stress-induced (11,15,22).…”

Section: Integro-differential Equation Modelmentioning

confidence: 99%

“…This idea is supported by several observations. First, in response to stress caused by exposure to chemotherapeutic agents, damage to DNA is a common event and can activate the DNA damage response-a process that has been associated with cellcycle arrest in lung cancer cells (22,23)-until either the DNA can be repaired, or apoptosis is triggered. Second, one of the main chemotherapy drugs used in the experiments of ref.…”

Section: Integro-differential Equation Modelmentioning

confidence: 99%

Emergence of Drug Tolerance in Cancer Cell Populations: An Evolutionary Outcome of Selection, Nongenetic Instability, and Stress-Induced Adaptation

et al. 2015

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In recent experiments on isogenetic cancer cell lines, it was observed that exposure to high doses of anticancer drugs can induce the emergence of a subpopulation of weakly proliferative and drug-tolerant cells, which display markers associated with stem cell-like cancer cells. After a period of time, some of the surviving cells were observed to change their phenotype to resume normal proliferation and eventually repopulate the sample. Furthermore, the drug-tolerant cells could be drug resensitized following drug washout. Here, we propose a theoretical mechanism for the transient emergence of such drug tolerance. In this framework, we formulate an individual-based model and an integro-differential equation model of reversible phenotypic evolution in a cell population exposed to cytotoxic drugs. The outcomes of both models suggest that nongenetic instability, stress-induced adaptation, selection, and the interplay between these mechanisms can push an actively proliferating cell population to transition into a weakly proliferative and drug-tolerant state. Hence, the cell population experiences much less stress in the presence of the drugs and, in the long run, reacquires a proliferative phenotype, due to phenotypic fluctuations and selection pressure. These mechanisms can also reverse epigenetic drug tolerance following drug washout. Our study highlights how the transient appearance of the weakly proliferative and drugtolerant cells is related to the use of high-dose therapy. Furthermore, we show how stem-like characteristics can act to stabilize the transient, weakly proliferative, and drug-tolerant subpopulation for a longer time window. Finally, using our models as in silico laboratories, we propose new testable hypotheses that could help uncover general principles underlying the emergence of cancer drug tolerance. Cancer Res; 75(6); 930-9. Ó2015 AACR.

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“…The activation of the Notch1 signaling pathway also has downstream effects on protein kinase casein kinase 2α (34), Ras (35) and tribbles homolog 3 (36). The activation of Notch1 may contribute to drug resistance in LAC, since the downregulation of Notch1 has been found to be effective during treatment with δ-tocotrienol (37)(38)(39), gefitinib (40,41), cisplatin (42) or pterostilbene (43). Blocking Notch1 has been identified to inhibit the growth of cluster of differentiation 133-positive cancer cells (44).…”

mentioning

confidence: 99%

Cigarette smoke induces the expression of Notch3, not Notch1, protein in lung adenocarcinoma

Cheng

Tan

et al. 2015

Oncology Letters

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Abstract. The aim of the present study was to determine the effect of cigarette smoke on the expression of Notch proteins in lung adenocarcinoma (LAC). Protein expression levels of Notch1 and Notch3 were analyzed using immunohistochemistry in 102 human LAC specimens. Of these, 52 were obtained from smokers and 50 from non-smokers. In addition, cigarette smoke extract (CSE) at varying concentrations (1, 2.5 and 5%) was administered to A549 cells. The expression of Notch1 and Notch3 protein was then detected by western blot analysis at different time points (0, 8, 24 and 48 h). Of the 102 LAC specimens, 42 (41.2%) were positive for Notch1 and 63 (61.8%) were positive for Notch3. There was no significant difference in the level of Notch1 expression between smokers and non-smokers with LAC (P>0.05). The positive rate and staining intensity of Notch3 expression were increased in the smokers compared with the non-smokers (P<0.05). The expression of Notch3 protein in A549 cells increased in a time-and dose-dependent manner following treatment with CSE, whilst the expression of Notch1 protein appeared stable. The results suggested that cigarette smoke was able to induce the expression of Notch3, not Notch1, protein in LAC. The data revealed an upregulation of Notch3 in LAC following cigarette smoke exposure. Such findings may provide a novel therapeutic target for the treatment of LAC.

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Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling

Cited by 189 publications

References 46 publications

γ-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway

γ-Secretase inhibitor DAPT sensitizes t-AUCB-induced apoptosis of human glioblastoma cells in vitro via blocking the p38 MAPK/MAPKAPK2/Hsp27 pathway

Emergence of Drug Tolerance in Cancer Cell Populations: An Evolutionary Outcome of Selection, Nongenetic Instability, and Stress-Induced Adaptation

Cigarette smoke induces the expression of Notch3, not Notch1, protein in lung adenocarcinoma

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