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Chemotherapeutic targeting of microtubules causes epidermal growth factor receptor dephosphorylation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
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(English)Article in journal (Other academic) Submitted
Abstract [en]

Microtubules are important structures for a range of cellular functions including cell division. Drugs that interfere with microtubule function can prevent cells from mitosis and various microtubule targeting drugs are used in a clinical setting. In the current study we investigated the sensitivity of oesophageal cancer cells to different microtubule targeting agents. As expected, experiments demonstrated that these agents in a dose-dependent manner inhibited survival and proliferation of oesophageal cancer cells and disrupted the microtubule network. Unexpectedly, experiments showed that microtubule destabilising agents inhibited phosphorylation and activation of the EGF-receptor, and that a tyrosine phosphatase inhibitor, sodium orthovanadate, could reverse the EGFR dephosphorylation. We propose a model in which disruption of the microtubule network leads to activation of a protein tyrosine phosphatase that can regulate EGFR phosphorylation and activation, indicating an additional mechanism of action of microtubule targeting agents.

Identifiers
URN: urn:nbn:se:uu:diva-152763OAI: oai:DiVA.org:uu-152763DiVA: diva2:413971
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2011-07-22Bibliographically approved
In thesis
1. Oesophageal Cancer – Novel Targets for Therapy: With focus on Hsp90, EGFR, LRIG, microtubule and telomerase
Open this publication in new window or tab >>Oesophageal Cancer – Novel Targets for Therapy: With focus on Hsp90, EGFR, LRIG, microtubule and telomerase
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Oesophageal cancer is a malignant and aggressive disease with very poor survival. The aim of this thesis was to evaluate novel therapeutic targets in oesophageal cancer.

In paper I, Hsp90 was expressed in all 81 oesophageal cancer tissues and also in nine oesophageal cancer cell lines. A specific Hsp90 inhibitor, 17-AAG, could efficiently inhibit cell proliferation, cell survival and sensitise oesophageal cancer cells to gamma photon irradiation. By inhibition of Hsp90 using 17-AAG, EGFR- and IGF-1R-mediated signalling was downregulated.

In paper II, tumour samples from 80 oesophageal cancer patients were investigated for the expression of EGFR and LRIG1-3. Based on a total score of intensity and expression fraction a trend towards survival differences was found for LRIG2 (p=0.18) and EGFR (p=0.09). Correlation analysis revealed a correlation between expression of EGFR and LRIG3 (p=0.0007). Significant correlations were found between LRIG1 mRNA expression levels and sensitivity to cisplatin (r = –0.74), docetaxel (r = –0.69), and vinorelbine (r = –0.82).

In paper III, microtubule targeting drugs podophyllotoxin (PPT), vincristine and docetaxel inhibited survival and proliferation of oesophageal cancer cells. Unexpectedly, experiments showed that microtubule destabilising agents inhibited EGFR phosphorylation and signalling. A tyrosine phosphatase inhibitor, sodium orthovanadate, was able to reverse the EGFR dephosphorylation.

In paper IV, imetelstat, a telomerase antagonist, inhibited telomerase activity, colony formation ability and decreased proliferation of oesophageal cancer cells. Inhibition of telomerase activity by imetelstat led to an increase of 53BP1 foci indicating induction of DSBs. Furthermore, the fraction and size of radiation-induced 53BP1 foci were increased by imetelstat pre-treatment.

In conclusion, Hsp90 and telomerase represent potential therapeutic targets in oesophageal cancer. And, the implication of EGFR and LRIG as prognostic factors is limited. Furthermore, disruption of the microtubule network may activate a protein tyrosine phosphatase that can regulate EGFR phosphorylation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 680
Keyword
Hsp90, EGFR, LRIG, microtubule, telomerase, oesophageal cancer, imetelstat, DNA double-strand break, 17-AAG, radiation, prognosis, radiosensitisation, microtubule targeting agents
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-152614 (URN)978-91-554-8100-1 (ISBN)
Public defence
2011-06-14, Auditorium Minus, Gustavianum, Akademigatan 3, 75310, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2011-05-24 Created: 2011-04-28 Last updated: 2011-07-01Bibliographically approved

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