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

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 (CoCl 2 ) 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-1a (HIF-1a) 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-1a-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-1a-dependent manner.

Preclinical Evaluation of Telomerase-Specific Oncolytic Virotherapy for Human Bone and Soft Tissue Sarcomas

“…Primary epithelial and nonepithelial malignant tumors frequently express CAR (23)(24)(25)(26)(27)(28)(29)(30). However, CAR expression can often be downregulated by tumor progression (45,46) or under hypoxic conditions (47), possibly leading to a low infection efficiency and resistance to OBP-301. Thus, for future clinical application of OBP-301, it may be necessary to overcome the resistance to OBP-301 that arises during tumor progression.…”

A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus

“…Our finding of heterogenous GFP expression in tumor tissues, which indicates heterogenous CAR expression, is consistent with a previously reported heterogeneity in CAR expression. 42 As several factors such as hypoxia 43 and cell cycle status 44 have been suggested to affect CAR expression in tumor cells, factors in the tumor microenvironment may be involved in the heterogenous CAR expression in tumor cells. The cells were incubated with a monoclonal anti-CAR (RmcB) antibody, followed by a FITC-labeled secondary antibody, and were analyzed using flow cytometry.…”

The Contribution of Ig-Superfamily and MARVEL D Tight Junction Proteins to Cancer Pathobiology

“…In contrast, others have labeled CAR as a potential tumor suppressor, in studies where its downregulation has been associated with increased proliferation (41)(42)(43), invasive phenotypes (44,45) and hypoxic conditions; which themselves downregulate the transcription of CAR (46). In gastric cancer cells CAR gene silencing has been shown to induce increased proliferation as well as migration and invasion, with the reverse occurring under CAR overexpression conditions (43).…”

“…However, the variable expression of CAR across cancer types and subtypes makes it important to establish individual patient expression levels before treatment, in order to determine those who will be most responsive to adenoviral gene therapies (41,42). Interestingly, the discovery that CAR expression may be influenced transcriptionally by hypoxic environments means that alternative adenoviruses may be required in cases where CAR expression is low; in order to select those capable of cell attachment via attachment/invasion co-receptors independent of CAR (46).…”