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Downregulation of the coxsackie and adenovirus receptor in cancer cells by hypoxia depends on HIF-1α

Cancer Gene Therapy volume 17, pages 141–146 (2010)Cite this article

Abstract

Loss of the coxsackie and adenovirus receptor (CAR) has been found in various human cancers. Underlying mechanisms, however, are still poorly understood. Therefore, the objective of this study was to investigate the function of hypoxia, a ubiquitous phenomenon in carcinomas, in CAR regulation. In our approach, hypoxia and treatment with cobalt-(II)-chloride (CoCl2) induced a downregulation of CAR protein and mRNA expression, as well as a suppression of CAR gene promoter activity in AGS (gastric), SW480 (colon) and PC3 (prostate) cancer cells. In line with these findings we noted a decreased adenoviral uptake under hypoxic conditions. Aiming to further elucidate the molecular basis of this observation, a full-length hypoxia-inducible factor-1α (HIF-1α) cDNA was ectopically overexpressed in the AGS cell line diminishing CAR expression and CAR gene promoter activity. In line with these findings, exposure of HIF-1α-deficient AGS cells to hypoxia did not alter CAR mRNA expression level. On the basis of these data, it may be suggested that loss of CAR in human cancer cell lines under hypoxic conditions occurs in an HIF-1α-dependent manner.

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Abbreviations

CAR:

coxsackie and adenovirus receptor

TJ:

tight junctions

HIF-1α:

hypoxia-inducible factor-1α

FCS:

fetal calf serum

GFP:

green fluorescent protein

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Acknowledgements

We thank Dr J Bergelson for providing the Chinese hamster ovary cells stably expressing human CAR (CHO-CAR), and Dr RC Pong and Dr JT Hsieh for providing the CAR gene promoter construct. Furthermore, we thank Dr Thorsten Cramer for helpful comments. This work was supported by a grant of the Deutsche Forschungsgemeinschaft to MA.

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Authors and Affiliations

  1. Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Charité Medical School, Campus Virchow, Berlin, Germany

    K Küster, A Koschel, N Rohwer, A Fischer & B Wiedenmann

  2. Department of Interdisciplinary Endoscopy, University Hospital Hamburg Eppendorf, Hamburg, Germany

    M Anders

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Correspondence to M Anders.

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Küster, K., Koschel, A., Rohwer, N. et al. Downregulation of the coxsackie and adenovirus receptor in cancer cells by hypoxia depends on HIF-1α. Cancer Gene Ther 17, 141–146 (2010). https://doi.org/10.1038/cgt.2009.49

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  • DOI: https://doi.org/10.1038/cgt.2009.49

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