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Oncotarget: Efavirenz induces DNA damage response pathway in lung cancer

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The cover for Issue 41 of Oncotarget features Figure 7, "IPA ATM-signaling pathway in (A) EFV treated MRC-5 and (B) A549 cells," recently published in "Efavirenz induces DNA damage response pathway in lung cancer" by Marima, et al. which reported that the cell-cycle related genes are potential gene targets in understanding the effects of efavirenz 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 and normal lung fibroblast cells.

The loss in nuclear integrity in response to EFV was detected by 4′, 6-diamidino-2-phenylindole 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.

Interestingly, the p53 signaling pathway was activated irrespective of the repressed ATM pathway in A549 cells as revealed by the Ingenuity Pathway Analysis.

Dr. Rahaba Marima from The University of Pretoria as well as The University of the Witwatersrand said, "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."

Figure 7: IPA ATM-signaling pathway in (A) EFV treated MRC-5 and (B) A549 cells. The green and the red colours indicate down and up-regulation. The activated p53 irrespective of the expression levels of ATM activates its downstream targets such as p21, GADD45A, BRCA1 and NBS, inhibiting cell cycle progression and initiating DNA repair and growth arrest mechanisms.

Xulu and Hosie showed that ARV drugs including EFV caused apoptosis in the Human Squamous Cell carcinoma from Uterine Cervix cells and observed a change in morphological features such as rounding-up of cells, retraction of filopodia, blebbing and maintenance of plasma membrane integrity- characteristic features of apoptosis.

Due to the fact that the cell cycle is a tightly regulated process, eukaryotic cells respond to external stimuli such as DNA damage by activating signaling pathways that promote cell cycle arrest and DNA repair.

A previous study performed by the Marima Research group, involved assessing the effects of EFV on lung cancer cells at the cellular level on the physiological health of treated cells.

To date, several studies including Hecht et al., have revealed the cytotoxic effects of EFV against several cancer cells, but to our knowledge, no study yet has shown the anti-proliferative effects of EFV on lung epithelial cancer cells in relation to primary lung fibroblast cells.

In conjunction with preceding studies on EFV′s cyto-and-genotoxicity, this Oncotarget study is the first to reveal EFV mediated ATM/ATR genotoxicity in lung cells.

"In conjunction with preceding studies on EFV′s cyto-and-genotoxicity, this Oncotarget study is the first to reveal EFV mediated ATM/ATR genotoxicity in lung cells"

The Marima Research Team concluded in their Oncotarget Research Paper that the treatment of MRC-5 and A549 cells with EFV alters the gene expression of important factors that are essential in the maintenance of genomic stability in relation to the cell cycle.

This is particularly observed in the cancerous cells, with the significant down-regulation of AURKB and MAD2L2. Even though the normal p53 expression was shown here, p27, CASP3, Cyclin G1 and G2, NBN, RAD1 and RAD17 were significantly up-regulated.

Interestingly, the S-phase and DNA replication genes were downregulated; MCM4 in particular was –3.65 significantly down-regulated.

Depending on the severity of these effects in the physiological health of normal cells, EFV poses as a promising drug that can be used in synergy with chemo/radiotherapy.

Posttranscriptional gene regulation targeted by EFV in lung cells would also be interesting to pursue.

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

Full text - https://www.oncotarget.com/article/27725/text/

Correspondence to - Rahaba Marima - rahaba.marima@up.ac.za

Keywords - efavirenz, cell cycle, differential gene expression, DNA damage response pathway, lung cancer

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