Abstract
BackgroundTumour hypoxia promotes radioresistance and is associated with poor prognosis. The transcription factor Aryl hydrocarbon receptor nuclear translocator (ARNT), also designated as Hypoxia-inducible factor (HIF)-1β, is part of the HIF pathway which mediates cellular adaptations to oxygen deprivation and facilitates tumour progression.The subunits HIF-1α and ARNT are key players within this pathway. HIF-1α is regulated in an oxygen-dependent manner whereas ARNT is considered to be constitutively expressed. However, there is mounting evidence that certain tumour cells are capable to elevate ARNT in hypoxia which suggests a survival benefit.Therefore the objective of this study was to elucidate effects of an altered ARNT expression level on the cellular response to radiation.MethodsDifferent human cell lines (Hep3B, MCF-7, 786-Owt, 786-Ovhl, RCC4wt and RCC4vhl) originating from various tumour entities (Hepatocellular carcinoma, breast cancer and renal cell carcinoma respectively) were X-irradiated using a conventional linear accelerator. Knockdown of ARNT expression was achieved by transient siRNA transfection. Complementary experiments were performed by forced ARNT overexpression using appropriate plasmids. Presence/absence of ARNT protein was confirmed by Western blot analysis. Clonogenic survival assays were performed in order to determine cellular survival post irradiation. Statistical comparison of two groups was achieved by the unpaired t-test.ResultsThe results of this study indicate that ARNT depletion renders tumour cells susceptible to radiation whereas overexpression of this transcription factor confers radioresistance.ConclusionsThese findings provide evidence to consider ARNT as a drug target and as a predictive marker in clinical applications concerning the response to radiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-015-0539-9) contains supplementary material, which is available to authorized users.
Highlights
Tumour hypoxia promotes radioresistance and is associated with poor prognosis
In radioresistant malignancies such as hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) radiotherapy is primarily used in a palliative setting in order to control metastatic spread [4, 5]
Aryl hydrocarbon receptor nuclear translocator (ARNT) is generally considered as constitutively expressed but emerging evidence indicates the capability of certain tumour cells to upregulate ARNT in response to hypoxia
Summary
Tumour hypoxia promotes radioresistance and is associated with poor prognosis. HIF-1α is regulated in an oxygen-dependent manner whereas ARNT is considered to be constitutively expressed. Adjuvant radiotherapy reduces the risk of recurrence and improves overall survival [3]. In radioresistant malignancies such as hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) radiotherapy is primarily used in a palliative setting in order to control metastatic spread [4, 5]. Tumour hypoxia is considered as a prognostic parameter predicting poor overall- and disease-free survival independent of the tumour grade [6]
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