Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Wohlkoenig, C.
Mechanisms of hypoxia-induced chemoresistance
¿ role of IAP family members and VEGF
[ Dissertation ] Medical University of Graz; 2012. pp. 81
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- Autor*innen der Med Uni Graz:
- Wohlkönig Christoph
- Betreuer*innen:
- Huppertz Berthold
- Olschewski Horst
- Altmetrics:
- Abstract:
- Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers. Platinum-based chemotherapy represents the gold standard for treating NSCLC. However, the efficacy is limited partially due to primary chemotherapy resistance. Resistance to cisplatin is highly complex and may occur due to various reasons i.e. decreased accumulation of cisplatin or increased repair of DNA damage. In addition, hypoxia-induced chemotherapy-resistance may play a role. It is well acknowledged that in solid tumors hypoxic conditions prevail and that this contributes to treatment failure and bad prognosis. Hypoxia was found to induce apoptosis and thereby select for multi-resistent cells but also hypoxia-induced adaptive mechanisms leading to chemotherapy resistance have been described. However, the exact downstream mechanisms of hypoxia-induced chemotherapy resistance remain to be elucidated. For this PhD thesis we created an NSCLC cell line model which suggested that the growth rate of NSCLC cells is diminished in hypoxia but cells do not undergo apoptosis in hypoxia per se. However, NSCLC cells in hypoxia develop a strong resistance to cisplatin-induced apoptosis. We showed for the first time that re-oxygenation in NSCLC cell lines reversed cisplatin resistance after about 24 h. This indicates a reversible hypoxia-specific cellular adaptation process leading to resistance against cisplatin. Hypoxia-induced growth rate reduction was mimicked by means of serum-starvation but did not induce cisplatin resistance. With this experiment we demonstrated that hypoxia-induced cisplatin resistance is independent of growth rate. Furthermore we showed that hypoxia-induced chemotherapy resistance was associated with down-regulation of the pro-apoptotic BCL-2-family-protein BAX in A549 cells. Literature data suggested that the strongly hypoxia-regulated vascular endothelial growth-factor (VEGF) pathway might have pro-survival effects on cancer cells through an autocrine signalling loop and could thus play a role in hypoxia-induced chemoresistance. We showed that NSCLC cells expressed VEGF receptors and secreted VEGF, where the latter is indeed augmented in hypoxia. However, there was no pro-apoptotic role of autocrine VEGF signalling in NSCLC lung cancer cell lines. This challenges the hypothesis from the literature that VEGF inhibitors act not only anti-angiogenic but also pro-apoptotic.