Abstract
Retinoblastoma is the most common pediatric intraocular malignant tumor. Unfortunately, low cure rates and low life expectancy are observed in low-income countries. Thus, alternative therapies are needed for patients who do not respond to current treatments or those with advanced cases of the disease. Ether à-go-go-1 (Eag1) is a voltage-gated potassium channel involved in cancer. Eag1 expression is upregulated by the human papilloma virus (HPV) oncogene E7, suggesting that retinoblastoma protein (pRb) may regulate Eag1. Astemizole is an antihistamine that is suggested to be repurposed for cancer treatment; it targets proteins implicated in cancer, including histamine receptors, ATP binding cassette transporters, and Eag channels. Here, we investigated Eag1 regulation using pRb and Eag1 expression in human retinoblastoma. The effect of astemizole on the cell proliferation of primary human retinoblastoma cultures was also studied. HeLa cervical cancer cells (HPV-positive and expressing Eag1) were transfected with RB1. Eag1 mRNA expression was studied using qPCR, and protein expression was assessed using western blotting and immunochemistry. Cell proliferation was evaluated with an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. RB1 transfection down-regulated Eag1 mRNA and protein expression. The human retinoblastoma samples displayed heterogeneous Eag1 mRNA and protein expression. Astemizole decreased cell proliferation in primary retinoblastoma cultures. Our results suggest that Eag1 mRNA and protein expression was regulated by pRb in vitro, and that human retinoblastoma tissues had heterogeneous Eag1 mRNA and protein expression. Furthermore, our results propose that the multitarget drug astemizole may have clinical relevance in patients with retinoblastoma, for instance, in those who do not respond to current treatments.
Highlights
Retinoblastoma is the principal pediatric intraocular malignant tumor [1]
We discovered that normal human keratinocytes do not express Eag1 mRNA, but a very high Eag1 expression was found when these cells were transfected with the human papilloma virus (HPV) oncogenes E6 and/or E7 [26]
New therapeutic approaches for patients with retinoblastoma who do not respond to current treatments or those with advanced disease, as well as molecular insights into the gene expression regulation by retinoblastoma, are needed
Summary
Retinoblastoma is the principal pediatric intraocular malignant tumor [1]. Patients who had a bilateral retinoblastoma in childhood have an elevated risk to develop other tumors [3,4]. The retinoblastoma gene (RB1) was the first tumor suppressor to be described [5]. The corresponding encoded Rb protein (pRb) binds to several proteins including different transcription factors like E2F, snRNA-activating protein complex (SNAPc), TATA-binding protein (TBP), and Brahma-related gene (BRG) [6,7]. PRb has a very important role in cell proliferation, differentiation, and apoptosis, both in normal cells and different cancers [9]. Retinoblastoma samples share a common miRNA expression profile, and some mRNA targets of these miRNAs include RB1, as well as other tumor suppressor genes [10]
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