INPP4B overexpression enhances the antitumor efficacy of PARP inhibitor AG014699 in MDA-MB-231 triple-negative breast cancer cells

Abstract

Although preclinical and clinical studies on poly-(adenosine diphosphate ribose) polymerase (PARP) inhibitor alone or in combination with DNA-damaging agents have shown promising results, further research to improve and broaden the application scope of this therapeutic approach is needed. The main aim of this study was to evaluate whether overexpressing inositol polyphosphate 4-phosphatase type II (INPP4B) gene, a novel tumor suppressor gene negatively regulating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, could enhance the antitumor efficacy of PARP inhibitor AG014699 used in the treatment of triple-negative breast cancer (TNBC). Here in this report, we used a TNBC cell line MDA-MB-231 without expression of INPP4B as the study model and a lentiviral system to stably overexpress INPP4B gene in MDA-MB-231 cells. We detected that the overexpression of INPP4B could significantly suppress cell proliferation and block cell cycle progression in G1 phase via decreasing the protein level of phosphorylated AKT. It is further revealed that PARP inhibitor AG014699 induced DNA damage conferring a G2/M arrest and decreased cell viability, which is paralleled by the induction of apoptosis. However, PARP inhibitor AG014699 could activate the PI3K/AKT signaling pathway activity and partially offset its therapeutic efficacy. In our study, a significant enhancement of proliferation inhibition was observed when INPP4B overexpression was combined with PARP inhibitor AG014699 in comparison with either single treatment. The suppression of PI3K/AKT pathway caused by the overexpression of INPP4B contributed to the enhanced antitumor efficacy of the combined therapy. Our in vitro results indicated that this experimental therapeutic strategy combining INPP4B overexpression and PARP inhibitor AG014699 might be of potential therapeutic value as a new strategy for the treatment of patients with TNBC and is worthy of further study.