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. 2022 Apr 13:2022:6048017.
doi: 10.1155/2022/6048017. eCollection 2022.

Inhibition of APE1 Expression Enhances the Antitumor Activity of Olaparib in Triple-Negative Breast Cancer

Dan Jian  1 , Xue-Mei Li  1 , Nan Dai  1 , Dan-Dan Liang  1 , Gang Zhang  2 , Cheng-Yi Mao  3 , Dong Wang  1 , Guan-Bin Song  4 , Meng-Xia Li  1 , Hao Luo  1   4
Affiliations

Inhibition of APE1 Expression Enhances the Antitumor Activity of Olaparib in Triple-Negative Breast Cancer

Dan Jian et al. Evid Based Complement Alternat Med. .

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that is prone to recurrence and metastasis. Because of the lack of expression of estrogen receptor (ER) and progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in TNBC, treatment methods are greatly limited. In this study, the proliferation inhibition and apoptosis-inducing effects of PARP1 inhibitors in TNBC breast cancer cells and in vivo xenograft animal models were examined to investigate the molecular role of APE1 in PARP1-targeted therapy. In TNBC patients, the expression of APE1 and PARP1 were positively correlated, and high expression of APE1 and PARP1 was associated with poor survival of TNBC. Our results indicated that knockdown APE1 could increase the sensitivity of olaparib in the treatment of TNBC. In conclusion, the results of this study will not only clarify the molecular role of APE1 in PARP1-targeted therapy for TNBC but also provide a theoretical basis for the future clinical application of targeting APE1 and PARP1 in the treatment of refractory TNBC.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
The correlation between APE1 and PARP1 expression in TNBC patients. (a) The TCGA datasets examined the expression of APE1 and PARP1 in TNBC. (b) The TCGA datasets analyzed the correlation of APE1 and PARP1 in 134 TNBC. (c) The 60 clinical pathological tissue samples tested by immunohistochemical to analyze the correlation of APE1 and PARP1 expression. (d) The histogram of APE1 and PARP1 expression.
Figure 2
Figure 2
High expression of APE1 and PARP1 are associated with poor prognosis of TNBC patients (a) The Kaplan–Meier survival analyzed the relationship between the expression of APE1 and TNBC patient survival. (b) The Kaplan–Meier survival analyzed the relationship between the expression of PARP1and TNBC patients' survival. (c) The influence of the expression of APE1 and PARP1 on the three-year survival rate of TNBC patients.
Figure 3
Figure 3
The selection of experimental cells and detection of cell growth. (a) RT-PCR examined the expression levels of APE1 in MCF10A, MDA-MB-231, MDA-MB-436, and MCF-7 cell lines. (b) Western blotting examined the expression levels of APE1 in MCF10A, MDA-MB-231, MDA-MB-436, and MCF-7 cell lines. (c) Western blotting examined the expression levels of APE1 after transfection of siRNA. (d) CCK-8 examined the effect of siAPE1 and olaparib on cell growth in MDA-MB-231 and MDA-MB-436 cell lines.
Figure 4
Figure 4
Inhibition of APE1 expression increases the apoptosis and cell cycle arrest of TNBC cells. (a) Flow cytometry examined the effect of siAPE1 and olaparib on cell apoptosis in MDA-MB-231 and MDA-MB-436 cell lines. (b) Flow cytometry examined the effect of siAPE1 and olaparib on cell cycle arrest in MDA-MB-231 and MDA-MB-436 cell lines.
Figure 5
Figure 5
Combination of APE1 inhibition and olaparib treatment significantly suppress tumor growth in the xenograft mouse model. (a) Xenograft figure. (b) Tumor volume in xenografts. MDA-MB-231 cells were transfected with the shAPE1 or treated with the PARP1 inhibitor olaparib. (c) Xenograft weight. (d) The mouse bodyweight.
Figure 6
Figure 6
Immunohistochemistry assays of Ki-67, APE1, and PARP1expression in vivo (200×).
Figure 7
Figure 7
Inhibition of APE1 expression promotes DNA damage caused by PARP1 inhibitors. (a) Comet assay showed that suppression of APE1 significantly stimulated radiation-induced DNA damage compared to control in MDA-MB-231 cells. (b) Western blotting showed that inhibition of APE1 expression can further increase the expression of γH2AX and regulate the expression of apoptosis-related protein Bcl2 and Bax under olaparib treatment. (c) Immunofluorescence analysis of γH2AX levels further confirmed that combination of APE1 inhibition and olaparib treatment promotes DNA damage. (d) A schematic regulatory mechanism showing that inhibition of APE1 expression enhances the antitumor activity of olaparib.
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