We reported that APE1 overexpression was associated with cisplatin resistance in lung cancer . However, the detailed mechanism of APE1 in cisplatin resistance remains elusive. In this study, we have found that cytoplasmic APE1 can cause resistance to cisplatin by upregulating COX-2 expression in lung cancer. Additionally, cytoplasmic APE1 expression is important in the occurrence of poor prognosis in lung cancer. Thus, we conclude that cytoplasmic APE1 can predict certain prognostic outcomes for lung cancer patients. Specifically, cytoplasmic APE1 expression can be used as a new method of identifying lung cancer patients with high tumor metastasis risk. These findings underscore the role of cytoplasmic APE1 expression in the development and progression of lung cancer.
Several reports have documented the associations between cytoplasmic APE1 expression and lung tumor aggressiveness, patient survival and relapse in lung cancer; additionally, patient prognosis in human epithelial ovarian cancer and anti-inflammatory activity in cultured endothelial cells have also been linked to cytoplasmic APE1 levels [7, 15–17]. In this study, we explored the role of cytoplasmic APE1 in the malignant phenotype of lung cancer in vitro and in vivo. Our results demonstrated that cytoplasmic APE1 can promote lung cancer cell growth and aggressiveness by inactivating the Akt/β-catenin signaling pathway by increasing COX-2 levels.
Cytoplasmic APE1 activity could be the major factor in cisplatin resistance induced by the overexpression of APE1. In our results, cell lines with cisplatin resistance had high cytoplasmic APE1 levels, and upregulation of cytoplasmic APE1 in cisplatin-sensitive cells caused resistance to cisplatin. Lower expression of cytoplasmic APE1 in lung cancer tissues was linked to better OS in patient samples. These results are entirely consistent with our earlier research that showed that cisplatin treatment increases APE1 expression and that inhibiting APE1 expression significantly increases the sensitivity of lung cancer cells to cisplatin [11, 18]. Clinical data analysis showed that survival prognosis was significantly better in lung cancer patients with low APE1 than in those with high APE1 expression levels . The role of APE1 in cisplatin resistance can at least partially attributed to increased cytoplasmic APE1 expression.
The activated Akt/β-catenin signaling pathway plays an important role in enhancing the malignant phenotype of human cancer [19, 20]. It has been reported that COX-2 indirectly regulates the Akt/β-catenin signaling pathway, while activated Akt/β-catenin signaling is strongly involved in cancer cisplatin resistance [21, 22]. The associations between the inhibition of Cox-2 expression, COX-2 inhibitors and cisplatin therapy resistance have been universally confirmed. Akt/β-catenin is one of the downstream signaling molecules activated by COX-2 in lung cancer malignancy that is mediated by cytoplasmic APE1.
The main purpose of our study was to explore the role of cytoplasmic APE1 in cisplatin resistance. Two critical questions were raised. First, cytoplasmic APE1 may have two functions: overexpression of cytoplasmic APE1 activated the COX-2/Akt/β-catenin signaling pathway and promoted cell proliferation and invasion, but overexpression of cytoplasmic APE1 induced by cisplatin played another role. Therefore, we believe that cytoplasmic APE1 may not only promote cell proliferation and invasion, but also reduce the toxicity of cisplatin by other mechanisms. Second, the mechanism by which cisplatin increased the expression of cytoplasmic of APE1 may be through inducing APE1-C65 site mutations. C65 is located within adjacent strands in the middle of one of the beta sheets within APE1, and the APE1-C65s site mutation causes a significant loss of the redox activity of APE1, which may cause the expression of cytoplasmic APE1. Both the APE1-C65 site mutation and cisplatin increased the expression of cytoplasmic APE1 and inhibited the COX-2/Akt/β-catenin signaling pathway. Moreover, cisplatin enhanced APE1-C65 site mutation-mediated inhibition of the COX-2/Akt/β-catenin signaling pathway. Previous studies have suggested that mutation of the N-terminus of APE1 induces cytoplasmic APE1 expression, specifically in the case of the C65 mutation, which is involved in cell proliferation . However, our study confirmed that cytoplasmic APE1 can cause cisplatin resistance by activating the COX-2/Akt/β-catenin signaling pathway, and the detailed relationships among cisplatin, APE1-C65 site mutations and cytoplasmic APE1 required further study.