Cytoplasmic APE1 promotes resistance response in osteosarcoma patients with cisplatin treatment

Abstract

Chemotherapy resistance has become a hold back and major clinical challenge in osteosarcoma cancer. The alteration and subcellular distribution of apurinic/ apyrimidinic endonuclease 1 (APE1) has been reported to be involved in chemotherapy resistance in many cancers. Here, we report that the cytoplasmic distribution of APE1 plays a key role in the sensitivity of combination platinum chemotherapy in osteosarcoma. Interestingly, the prevalence of cisplatin-induced DNA damage and apoptosis in low cytoplasmic APE1 osteosarcoma cell lines was higher than in high expression of cytoplasmic APE1 cell lines. Overexpression of cytoplasmic APE1 protected the osteosarcoma cells from CDDP-induced apoptosis. In addition, clinical data also show that the level of cytoplasmic APE1 was negatively associated with sensitivity to combination chemotherapy of cisplatin in osteosarcoma patients. Our findings suggest that cytoplasmic APE1 plays a significant role in chemotherapy resistance. This role is a supplement to the extranuclear function of APE1, and cytoplasmic APE1 expression level could be a promising predictor of platinum treatment prognosis for osteosarcoma patients. K E Y W O R D S APE1, cisplatin resistance, cytoplasmic, predictor 1 | INTRODUCTION Osteosarcoma has become the most common primary malignant bone tumor, mainly in adolescent and young patients. 1,2 Cisplatin is one of the traditional chemotherapeutic agents used for osteosarcoma treatment. The mechanism of toxicity cisplatin is crosslinking DNA and formed DNA-cisplatin adducts, which in turn induce DNA damage. 3 Platinum-based drugs are the standard first-line agents used alone or in combination with other drugs for osteosarcoma treatment. 4,5 However, the present protocols seem to have reached a plateau, 6 which may be associated with chemotherapy resistance. The molecular mechanisms of cisplatin resistance are complex and usually associated with a reduction in the intracellular accumulation of the platinum compounds and an increase in DNA damage repair. 3 Chemotherapy resistance has been linked with poor prognosis. Human apurinic/apyrimidinic endonuclease 1 (APE1/Ref-1) is a multifunctional protein that has both DNA damage repair and redox functions. As an essential enzyme in DNA base excision repair (BER), APE1 is involved in repairing DNA damage, creating an abasic site (apurinic/apyrimidinic, AP site) caused by oxidizers and alkylating agents. 7 APE1 is the key regulator in the cellular oxidative stress pathway, which maintains the activity of numerous cellular transcription factors, such as AP-1, NF-κB, Myb, HIF-1α, HLF, PAX, and p53, through keeping specific cysteine residues in the DNA binding domain reduced state. Moreover, some of these transcription factors are closely related to chemotherapy resistance. 8-10List of Abbreviations: AMLs, acute myeloid leukemias; Ang II, angiotensin II; AP sites, apurinic/apyrimidinic sites; AP-1, activator protein 1; APE1, apurinic/apyrimidinic endonuclease; BER, base excision repair; GADD45α, DNA damage-inducible pr...

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

“…This suggests that cisplatin can worsen pulmonary fibrosis in cancer patients [ 67 ]. In addition, cytoplasmic APE1 has been shown to promote cisplatin resistance in osteosarcoma and lung cancer cells [ 68 , 69 ] ( Figure 2 ). Similarly, POLβ P242R germline mutation has been associated with poor response to cisplatin treatment in patients with lung cancer [ 70 ] ( Figure 2 ).…”

APE1/Ref-1 – One Target with Multiple Indications: Emerging Aspects and New Directions

“…APE1 when methylated at R301 (Arginine 301) [24] translocates to the mitochondria [25] through the mitochondrial intermembrane space import and assembly protein 40 (MIA) pathway [26] and is responsible for maintaining mitochondrial DNA (mtDNA) integrity under oxidative stress and drives mitochondrial respiration [25]. Other studies have shown that mitochondrial APE1 decreases reactive oxygen species (ROS) generation in osteosarcoma cancer cells thereby promoting cisplatin resistance [27]. Endogenous ROS is a constant threat to mtDNA and reports show that both truncated and full-length APE1 have been found to be capable of repairing mtDNA through its endonuclease activity [28][29][30].…”