BAG1, MGMT, FOXO1, and DNAJA1 as potential drug targets for radiosensitizing cancer cell lines

Abstract

Background and purpose

Activation of some signaling pathways can promote cell survival and have a negative impact on tumor response to radiotherapy. Here, the role of differences in expression levels of genes related to the poly(ADP-ribose) polymerase-1 (PARP-1), heat shock protein 90 (Hsp90), B-cell lymphoma 2 (Bcl-2), and phosphoinositide 3-kinase (PI3K) pathways in the survival or death of cells following X-ray exposure was investigated.

Methods

Eight human cell cultures (MCF-7 and MDA-MB-231: breast cancers; MCF-12A: apparently normal breast; A549: lung cancer; L132: normal lung; G28, G44 and G112: glial cancers) were irradiated with X-rays. The colony-forming and real-time PCR based on a custom human pathway RT² Profiler PCR Array assays were used to evaluate cell survival and gene expression, respectively.

Results

The surviving fractions at 2 Gy for the cell lines, in order of increasing radioresistance, were found to be as follows: MCF-7 (0.200 ± 0.011), G44 (0.277 ± 0.065), L132 (0.367 ± 0.023), MDA-MB-231 (0.391 ± 0.057), G112 (0.397 ± 0.113), A549 (0.490 ± 0.048), MCF-12A (0.526 ± 0.004), and G28 (0.633 ± 0.094). The rank order of radioresistance at 6 Gy was: MCF-7 < L132 < G44 < MDA-MB-231 < A549 < G28 < G112 < MCF-12A. PCR array data analysis revealed that several genes were differentially expressed between irradiated and unirradiated cell cultures. The following genes, with fold changes: BCL2A1 (21.91), TP53 (8743.75), RAD51 (11.66), FOX1 (65.86), TCP1 (141.32), DNAJB1 (3283.64), RAD51 (51.52), and HSPE1 (12887.29) were highly overexpressed, and BAX (–127.21), FOX1 (–81.79), PDPK1 (–1241.78), BRCA1 (–8.70), MLH1 (–12143.95), BCL2 (–18.69), CCND1 (–46475.98), and GJA1 (–2832.70) were highly underexpressed in the MDA-MB-231, MCF-7, MCF-12A, A549, L132, G28, G44, and G112 cell lines, respectively. The radioresistance in the malignant A549 and G28 cells was linked to upregulation in the apoptotic, DNA repair, PI3K, and Hsp90 pathway genes BAG1, MGMT, FOXO1, and DNAJA1, respectively, and inhibition of these genes resulted in significant radiosensitization.

Conclusions

Targeting BAG1, MGMT, FOXO1, and DNAJA1 with specific inhibitors might effectively sensitize radioresistant tumors to radiotherapy.

Keywords:

• PARP-1
• PI3K
• Hsp90
• Bcl-2
• radioresistance

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported in part by the South African National Research Foundation (NRF) Grants [No. 85703 and No. 92741] to JA. Bursaries from NRF, the Faculty of Medicine and Health Sciences (Stellenbosch University) to BM and the Harry Crossley Foundation (HCF) grants are also acknowledged.

Notes on contributors

Bayanika Manunu

Bayanika Manunu, PhD, is a doctoral graduate of radiobiology with molecular and cell biology expertise.

Antonio M. Serafin

Antonio M. Serafin, PhD, is a retired researcher with skills in cell biology and radiation biology.

John M. Akudugu

John M. Akudugu, PhD, is a Professor of Radiobiology.