Efavirenz induces DNA damage response pathway in lung cancer.

Rahaba Marima,Zodwa Dlamini,Rodney Hull,Clement Penny

doi:10.18632/oncotarget.27725

Rahaba Marima, Zodwa Dlamini + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.27725

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Abstract

The cell-cycle related genes are potential gene targets in understanding the effects of efavirenz (EFV) in lung cancer. The present study aimed at investigating the expression changes of cell-cycle related genes in response to EFV drug treatment in human non-small cell lung carcinoma (A549) and normal lung fibroblast (MRC-5) cells. The loss in nuclear integrity in response to EFV was detected by 4′, 6-diamidino-2-phenylindole (DAPI) staining. Gene expression profiling was performed using human cell cycle PathwayFinder RT2 Profiler™ PCR Array. The expression changes of 84 genes key to the cell cycle pathway in humans following EFV treatment was examined. The R2 PCR Array analysis revealed a change in expression of selected gene targets (including MAD2L2, CASP3, AURKB). This change in gene expression was at least a two-fold between test (EFV treated) and the control. RT-qPCR confirmed the PCR array data. In addition to this, the ATM signaling pathway was shown to be upregulated following EFV treatment in MRC-5 cells. In particular, ATM’s upstream activation resulted in p53 upregulation in normal lung fibroblasts. Interestingly, the p53 signaling pathway was activated irrespective of the repressed ATM pathway in A549 cells as revealed by the Ingenuity Pathway Analysis (IPA). These EFV effects are similar to those of ionizing radiation and this suggests that EFV has anti-tumour properties.

Highlights

The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) is frequently used in human immunodeficiency virus (HIV) treatment, and forms part of the first-line Highly Active Antiretroviral Treatment (HAART) treatment against HIV/AIDS [1]
Following on the aforementioned observations relating to loss of nuclear integrity, a specific gene panel was employed here to interrogate changes in the expression of cell cycle related genes in response to EFV treatment
The balance between cyclins/cyclin-dependent kinase (CDK) and CDKIs is essential in maintaining cellular homeostasis, and determines cell fate, that is, proliferation, senescence or cell death

Summary

Introduction

The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) is frequently used in human immunodeficiency virus (HIV) treatment, and forms part of the first-line Highly Active Antiretroviral Treatment (HAART) treatment against HIV/AIDS [1]. EFV has selective cytotoxic effects against different cancer cells [2, 3]. This includes cancers such as colorectal, glioblastoma, and pancreatic, while sparing human primary fibroblast cells [2]. Tumour growth in mouse models treated with EFV was shown to be reduced [4, 5]. Jin et al, (2016) revealed that EFV reduced proliferation of neuronal stem cell and increased apoptosis by increasing the expression of BAX and CASP3 [6]. Moraes-Filho et al, (2017) demonstrated that EFV at high doses induced genotoxicity in Drosophila Melanongaster [7]

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