Abstract
BackgroundIonizing irradiation is a commonly accepted treatment modality for lung cancer patients. However, the clinical outcome is hampered by normal tissue toxicity and tumor hypoxia. Since tumors often have higher levels of active heat shock protein 90 (Hsp90) than normal tissues, targeting of Hsp90 might provide a promising strategy to sensitize tumors towards irradiation. Hsp90 client proteins include oncogenic signaling proteins, cell cycle activators, growth factor receptors and hypoxia inducible factor-1α (HIF-1α). Overexpression of HIF-1α is assumed to promote malignant transformation and tumor progression and thus might reduce the accessibility to radiotherapy.Methodology/Principal FindingsHerein, we describe the effects of the novel Hsp90 inhibitor NVP-AUY922 and 17-allylamino-17-demethoxygeldanamycin (17-AAG), as a control, on HIF-1α levels and radiosensitivity of lung carcinoma cells under normoxic and hypoxic conditions. NVP-AUY922 exhibited a similar biological activity to that of 17-AAG, but at only 1/10 of the dose. As expected, both inhibitors reduced basal and hypoxia-induced HIF-1α levels in EPLC-272H lung carcinoma cells. However, despite a down-regulation of HIF-1α upon Hsp90 inhibition, sensitivity towards irradiation remained unaltered in EPLC-272H cells under normoxic and hypoxic conditions. In contrast, treatment of H1339 lung carcinoma cells with NVP-AUY922 and 17-AAG resulted in a significant up-regulation of their initially high HIF-1α levels and a concomitant increase in radiosensitivity.Conclusions/SignificanceIn summary, our data show a HIF-1α-independent radiosensitization of normoxic and hypoxic H1339 lung cancer cells by Hsp90 inhibition.
Highlights
Lung cancer is one of the most frequent tumors worldwide and patients with locoregionally advanced tumor stages are frequently treated with radiochemotherapy
hypoxia inducible factor-1a (HIF-1a) and hypoxia inducible factor (HIF)-2a protein levels were analyzed in EPLC-272H and H1339 lung cancer cells under normoxic ([O2] = 21%) and hypoxic ([O2] = 0.66%) conditions, in the presence and absence of two structurally distinct heat shock protein 90 (Hsp90) inhibitors, 17-AAG and NVP-AUY922
In order to explain the differential regulation of HIF-1a after treatment with Hsp90 inhibitors in H1339 and EPLC-272H lung cancer cells, we investigated the expression of Cullin 5 E3 ubiquitin ligase (Cul5), receptor of activated protein C kinase (RACK1) and Copper Metabolism MURR1 Domain containing 1 protein (COMMD1) which have been described to regulate the degradation of HIF-1a upon Hsp90 inhibition [16,17,18]
Summary
Lung cancer is one of the most frequent tumors worldwide and patients with locoregionally advanced tumor stages are frequently treated with radiochemotherapy. The adaptation of tumor cells to hypoxia is primarily mediated by stabilization of two hypoxia inducible factor (HIF) complexes, HIF-1 and HIF-2 [4]. HIF-1 and HIF-2 are heterodimeric transcription factors composed of a constitutively expressed b-subunit (HIF-1b/ARNT) and a HIF-a subunit (HIF-1a, HIF-2a), which is regulated by tissue oxygen status. The HIF complex binds to the hypoxia responsive element (HRE) in the promoter region of oxygen-regulated genes and leads to their transcriptional activation. Since tumors often have higher levels of active heat shock protein 90 (Hsp90) than normal tissues, targeting of Hsp might provide a promising strategy to sensitize tumors towards irradiation. Hsp client proteins include oncogenic signaling proteins, cell cycle activators, growth factor receptors and hypoxia inducible factor-1a (HIF-1a). Overexpression of HIF-1a is assumed to promote malignant transformation and tumor progression and might reduce the accessibility to radiotherapy
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