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- Dreilich, Martin, et al.
(författare)
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Telomerase activity is not a key determinant of sensitivity to standard cytotoxic drugs in human esophageal carcinoma cell lines
- 2006
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 17:5, s. 503-509
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate if basal telomerase activity levels may predict sensitivity to cytotoxic drugs in a panel of human esophageal carcinoma cell lines. The TRAPeze telomerase detection assay was used to investigate telomerase activity in the cell lines. Cytotoxic drug sensitivity for 20 standard cytotoxic agents was assessed using the fluorometric microculture cytotoxicity assay (FMCA). Telomerase activity was detected in all cell lines with a broad range of activity levels. Drug sensitivity also varied considerably between the cell lines. Except for a P value towards a correlation between mitoxantrone and telomerase activity (P=0.054), no statistically significant correlation was found between telomerase activity levels and sensitivity to investigated drugs, including key drugs such as cisplatin (P=0.9), 5-fluorouracil (P=0.8) and doxorubicin (P=0.54). We therefore conclude that basal telomerase activity level is not a key determinant of sensitivity to standard cytotoxic drugs in esophageal carcinoma cell lines.
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| 2. |
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| 3. |
- Lindkvist, Anna, 1976-
(författare)
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Activity and Regulation of Telomerase in Malignant Cells
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An important step in tumorgenesis is the acquisition of cellular immortality. Tumor cells accomplish this by activating the enzyme telomerase, and thereby avoiding replicative senescence. The aim of this thesis was to study the activity and regulation of telomerase in a panel of malignant cell types.We found that TGF-β1 (transforming growth factor-β1) mediated differential effects on telomerase activity in five ATC (anaplastic thyroid carcinoma) cell lines. Cells that harbored a p53 mutation responded by up-regulation of telomerase activity after TGF-β1 treatment, whereas cell lines displaying wt p53 responded by down-regulation of telomerase activity. Thus, these results indicate a possible connection between p53 genotype and telomerase response to TGF-β1 treatment. Furthermore, the decreased telomerase activity appeared to be due to transcriptional repression of the hTERT promoter and the increased activity possibly involved hTERT activation via phosphorylation. We have previously shown that IFNs (interferons) sensitize MM (multiple myeloma) cells to Fas-mediated apoptosis. In the present investigation both IFN-α and IFN-γ down regulated telomerase activity in the MM cell line U-266-1970. The mechanism underlying the reduction of telomerase activity by IFN was shown to be transcriptional repression of the hTERT gene. We suggest that one potential mechanism whereby IFN sensitize MM cells to Fas-mediated apoptosis is by repressing hTERT activity at the transcriptional level. In the next study we demonstrated that basal telomerase activity is not a key determinant of sensitivity to cytotoxic drugs in ESCC (esophageal squamous cell carcinoma) cell lines. Furthermore, we observed no correlation between c-Myc amplification, p53 mutations and high telomerase activity levels in these cell lines. Finally, neuroblastoma cell lines were shown to up-regulate telomerase activity in response to hypoxic exposure and the main regulatory mechanism was not mediated by increased hTERT mRNA expression. This finding might constitute an adaptive stress response of tumor cells exposed to hypoxia.
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| 4. |
- Lindkvist, Anna, et al.
(författare)
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Differential effects of TGF-beta1 on telomerase activity in thyroid carcinoma cells
- 2005
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 338:3, s. 1625-1633
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate the effect of transforming growth factor-beta1 (TGF-beta1) on telomerase activity in a panel of human anaplastic thyroid carcinoma (ATC) cell lines. Addition of TGF-beta1 decreased the telomerase activity in HTh 74 and KTC-1 cells, while in C 643 and HTh 7 an increased activity was observed. The decreased telomerase activity appeared to be due to transcriptional repression of the hTERT promoter. Addition of a PI-3 kinase inhibitor (LY294002) abrogated the stimulatory effect of TGF-beta1 on the telomerase activity, indicating the possible involvement of hTERT activation via phosphorylation. Furthermore, the MEK-inhibitor U0126 had similar effects suggesting dual regulatory mechanisms. Interestingly, the cell lines differed genetically in that ATC cell lines responding with increased telomerase activity harbored a p53 mutation. In conclusion, TGF-beta1 exerts opposing effects on telomerase activity in ATC cell lines, possibly reflecting deregulation of TGF-beta1 signaling in a more malignant genotype.
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