Efavirenz induces DNA damage response pathway in lung cancer
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Rahaba Marima1,2, Rodney Hull1, Zodwa Dlamini1,2 and Clement Penny2
1 SA-MRC/UP Precision Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Pan African Cancer Research Institute, Faculty of Health Sciences, University of Pretoria, Hatfield 0028, South Africa
2 Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown, 2193, South Africa
Keywords: efavirenz; cell cycle; differential gene expression; DNA damage response pathway; lung cancer
Received: April 14, 2020 Accepted: July 16, 2020 Published: October 13, 2020
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.
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