Radiosensitization to γ-Ray by Functional Inhibition of APOBEC3G

Abstract

The radiosensitization of tumor cells is one of the promising approaches for enhancing radiation damage to cancer cells and limiting radiation effects on normal tissue. In this study, we performed a comprehensive screening of radiosensitization targets in human lung cancer cell line A549 using an shRNA library and identified apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G: A3G) as a candidate target. APOBEC3G is an innate restriction factor that inhibits HIV-1 infection as a cytidine deaminase. APOBEC3G knockdown with siRNA showed an increased radiosensitivity in several cancer cell lines, including pancreatic cancer MIAPaCa2 cells and lung cancer A549 cells. Cell cycle analysis revealed that APOBEC3G knockdown increased S-phase arrest in MIAPaCa2 and G2/M arrest in A549 cells after γ-irradiation. DNA double-strand break marker γH2AX level was increased in APOBEC3G-knocked-down MIAPaCa2 cells after γ-irradiation. Using a xenograft model of A549 in mice, enhanced radiosensitivity by a combination of X-ray irradiation and APOBEC3G knockdown was observed. These results suggest that the functional inhibition of APOBEC3G sensitizes cancer cells to radiation by attenuating the activation of the DNA repair pathway, suggesting that APOBEC3G could be useful as a target for the radiosensitization of cancer therapy.

APOBEC3G protects the genome of human cultured cells and mice from radiation‐induced damage

“…In contrast, all the WT and 88% of the mA3‐knockout mice died or were euthanized prior to the end of the experiment. The findings recently reported by Tong and his coworkers [41] showing that inhibition of A3G radiosensitizes A3G‐expressing tumour cells, provide a solid support to our data presented here and in our previous publications [39,43].…”

“…Certainly, the involvement of A3G, F and H proteins in the inhibition of retro- element propagation is an additional important way by which these proteins protect the host's genome integrity, as exemplified by A3G's in vivo antiretroviral activity [23,57]. The fact that several normal tissues [58] and some genotoxic-resistant tumours express high amounts of A3G [39][40][41][42] led us to ask whether A3G supports the survival of cells and mice from genotoxic treatments, such as IR. To address this question, we utilized both cellular models and transgenic mice strains to demonstrate the pivotal role of A3G in promoting DSB repair.…”

“…Intriguingly, diffuse large B-cell lymphoma (DLBCL), several glioblastoma, lung adenocarcinoma and pancreatic cancer cell lines expressing high levels of A3G are resistant to chemo-and radiotherapies [39][40][41][42], suggesting additional roles for A3G. We have previously shown that cells expressing endogenous A3G are highly resistant to ionizing radiation (IR) compared to cells devoid of A3G [39,43].…”

Radioprotection and Radiosensitization: A Modern View on Radiomodulators in Pharmacology

“…Поэтому идут постоянный поиск и изучение новых подходов и биологических мишеней для реализации радиомодулирующих эффектов. Например, было показано, что изменение в работе фактора рестрикции APOBEC3G делает клетки более радиочувствительными (на модели ксенотрансплантата у мышей при раке легкого и поджелудочной железы) [39].Одним из белков-мишеней является сурвивин, который сверхэкспрессируется в опухолевых клетках человека. Данный белок является регулятором клеточного деления, апоптоза, а также участвует в регуляции клеточной миграции, приводящей к метастазированию [40].…”