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Anti-apoptotic and Pro-inflammatory Signaling in Cancer Cells : Status and Modulation by Chemotherapeutic Drugs

Anti-apoptotic and Pro-inflammatory Signaling in Cancer Cells : Status and Modulation by Chemotherapeutic Drugs

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IMRE, Gabriele, 2006. Anti-apoptotic and Pro-inflammatory Signaling in Cancer Cells : Status and Modulation by Chemotherapeutic Drugs

@phdthesis{Imre2006Anti--7880, title={Anti-apoptotic and Pro-inflammatory Signaling in Cancer Cells : Status and Modulation by Chemotherapeutic Drugs}, year={2006}, author={Imre, Gabriele}, address={Konstanz}, school={Universität Konstanz} }

2011-03-24T17:38:14Z eng The transcription factor nuclear factor kappa-B (NFkB) plays a pivotal role in the immune response but is also involved in cancer development and progression. In unstimulated cells NFkB is kept inactive in the cytoplasm by inhibitor of NFkB (IkB) proteins. Dysregulation of the pathway or activation of NFkB by chemotherapeutic agents may lead to cancer progression or drug resistance.<br />The NFkB activation status was investigated in human lung cancer, pancreatic cancer, and hematopoietic cancer cell lines. Non-small cell lung cancer (NSCLC) cells possess a functional NFkB pathway exhibiting basal NFkB activity in unstimulated cells and a strong increase upon stimulation. NFkB in small cell lung cancer (SCLC) cells could not be activated by tumor necrosis factor alpha (TNF-a) due to absence of the TNF-receptor 1 (TNF-R1). Other components of the pathway such as the inhibitor of NFkB kinase (IKK) complex or IkB-a were functional in SCLC, as topoisomerase poisons could activate the NFkB pathway in these cells.<br />Pancreatic cancer cells exhibited increased NFkB activity in unstimulated cells, possibly due to upstream activating signals. On the one hand, NFkB activity could be decreased by proteasome inhibition, yet on the other hand it could be further enhanced by TNF-a treatment.<br />Investigation of hematopoietic cancer cells demonstrated that Hodgkin s lymphoma, many B-cell lymphoma or multiple myeloma cell lines showed strong NFkB activity in untreated cells. There, cells acquired constitutive NFkB activity possibly due to mutations in the IkB-a protein or activation of upstream signals. Treatment with IKK inhibitors in above mentioned cell lines caused cellular toxicity, but EC50 was similar in all cell lines checked, independent of their kB activation status.<br />In lung cancer cells, activation of NFkB by cytotoxic drugs was confined to topoisomerase poisons such as etoposide or camptothecin, but could not be detected in cells incubated with DNA crosslinkers such as cisplatin or alkylating agents such as mafosfamide. Additionally, activation of NFkB by the topoisomerase poisons was cell line dependent.<br />Furthermore, the influence of histone deacetylase inhibitors (HDIs) on the NFkB pathway in human NSCLC cell lines was investigated. Incubation of NSCLC cells with HDIs reduced the responsiveness of NFkB to TNF-a. It was shown that this reduction was due to drastic downregulation of TNF-R1 by HDIs. After 24 hours of HDI treatment, mRNA levels of TNF-R1 were lowered to approx. 10%, protein levels and cell surface expression were decreased as well. Substantially, the consequence of this reduced TNF-R1 level was an almost abolished activation of the NFkB pathway by TNF-a through limited phosphorylation of the kinases IKK-a and IKK-b, yielding delayed and weakened phosphorylation and degradation of the inhibitor IkB-a. This resulted in reduced NFkB translocation and DNA binding, and strongly diminished target gene expression upon stimulation. Downregulation of TNF-R1 by HDIs could also be shown for other tumor entities and normal cell lines. In contrast, TRAIL-R2 expression was increased in response to HDIs. The results clearly demonstrate that HDIs do not directly affect NFkB or downstream signaling, but affect receptors at the cell surface due to a reprogramming of gene expression. application/pdf deposit-license 2011-03-24T17:38:14Z Antiapoptotische und proinflammatorische Signalgebung in Krebszellen: Status und Modulierbarkeit durch Chemotherapeutika 2006 Anti-apoptotic and Pro-inflammatory Signaling in Cancer Cells : Status and Modulation by Chemotherapeutic Drugs Imre, Gabriele Imre, Gabriele

Dateiabrufe seit 01.10.2014 (Informationen über die Zugriffsstatistik)

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