Apurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

/pdf/small-molecule-inhibition-of-ape1-induces-apoptosis-gn7cbuzst7.pdf

Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer.

Sorafenib is currently the standard chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC). But its efficacy requires improvement, it is imperative to seek therapeutic strategies that combine sorafenib with other anticancer agents. In this study we investigated the synergistic anticancer effect of combining sorafenib and artesunate, an anti-malaria drug derivative, against HCC in vitro and in vivo. We first showed that artesunate (1–100 μM) alone dose-dependently inhibited the proliferation of five HCC cell lines tested with IC50 values of around 100 μM. Artesunate treatment dose-dependently increased the ROS level in both HuH7 and Hep3B cells; addition of NAC significantly ameliorated the antiproliferation effect of artesunate against HuH7 and Hep3B cells. Then we demonstrated that combination of sorafenib and artesunate exerted synergistic antiproliferation effect and induced synergistic apoptosis in HCC cell lines. In nude mice bearing Hep3B xenografts, combined administration of sorafenib and artesunate significantly enhanced the suppression on tumor growth. We further revealed that sorafenib dose-dependently decreased the levels of p-ERK and p-STAT3, whereas artesunate markedly increased the levels of p-ERK and p-STAT3 in HuH7 and Hep3B cells. When used in combination, sorafenib abolished artesunate-elevated levels of p-STAT3 and p-ERK. Moreover, pharmacological inhibition of ERK by inhibitor PD0325901 or STAT3 by inhibitor Stattic markedly enhanced the anticancer activity of artesunate, suggesting that suppression of ERK and STAT3 signaling by sorafenib contributes to the synergistic anticancer activity against HCC caused by combination of sorafenib and artesunate. Taken together, our results provide an evidence for possible use of sorafenib plus artesunate or artemisinin analogs for treatment of HCC in the future.

Synergistic antitumor activity of sorafenib and artesunate in hepatocellular carcinoma cells

APE1 is essential in cancer cells due to its central role in the Base Excision Repair pathway of DNA lesions and in the transcriptional regulation of genes involved in tumor progression/chemoresistance. Indeed, APE1 overexpression correlates with chemoresistance in more aggressive cancers, and APE1 protein-protein interactions (PPIs) specifically modulate different protein functions in cancer cells. Although important, a detailed investigation on the nature and function of protein interactors regulating APE1 role in tumor progression and chemoresistance is still lacking. The present work was aimed at analyzing the APE1-PPI network with the goal of defining bad prognosis signatures through systematic bioinformatics analysis. By using a well-characterized HeLa cell model stably expressing a flagged APE1 form, which was subjected to extensive proteomics analyses for immunocaptured complexes from different subcellular compartments, we here demonstrate that APE1 is a central hub connecting different subnetworks largely composed of proteins belonging to cancer-associated communities and/or involved in RNA- and DNA-metabolism. When we performed survival analysis in real cancer datasets, we observed that more than 80% of these APE1-PPI network elements is associated with bad prognosis. Our findings, which are hypothesis generating, strongly support the possibility to infer APE1-interactomic signatures associated with bad prognosis of different cancers; they will be of general interest for the future definition of novel predictive disease biomarkers. Future studies will be needed to assess the function of APE1 in the protein complexes we discovered. Data are available via ProteomeXchange with identifier PXD013368.

/pdf/architecture-of-the-human-ape1-interactome-defines-novel-385g5chnc9.pdf

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures.

Background Hepatocellular carcinoma (HCC) is one of the most common malignancies, and its global morbidity and mortality are increasing. Previous studies confirmed that miR-342 was involved in the development and progression of malignant tumors. However, the relationship between miR-342 and Wnt/β-catenin signaling pathway in HCC remains unknown. Materials and methods Cell viability was detected by MTT assay. Immunofluorescence staining was used to detect Brdu-positive cells and Western blot was used to detect the apoptotic proteins. Furthermore, linear correlation analysis was used to investigate the possible relationship between miR-342 and the downstream genes of Wnt/β-catenin signaling pathway in the progression of HCC. Results Over-expression of miR-342 significantly reduced cell proliferation and obviously increased apoptosis in HCC, while silencing of miR-342 showed an opposite effect on HCC cell proliferation and apoptosis. In addition, we found that the CXCL12 was the target gene of miR-342. This study also demonstrated that miR-342 up-regulation suppressed Wnt/β-catenin signaling pathway by inhibiting CXCL12 expression. Conclusion Up-regulation of miR-342 inhibited cell proliferation and induced cell apoptosis in HCC by inhibiting Wnt/β-catenin signaling pathway, suggesting that miR-342 might act as a promising tumor gene therapeutic target for HCC patients.

MiR-342 regulates cell proliferation and apoptosis in hepatocellular carcinoma through Wnt/β-catenin signaling pathway.

APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.

Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons

This research aimed to investigate the differential expression of apurinic-apyrimidinic endonuclease 1 (APE1) in hepatocellular carcinoma (HCC) tissues and cells and the effects on proliferation and apoptosis of cancer cells. Immunohistochemical techniques were used to detect the expression of APE1 in 80 cases of HCC and the corresponding paracancerous tissue microarrays; meanwhile, Western blots were used to detect the expression of APE1 in both human HCC BEL-7402, BEL-7405, HCC-9204, Hep3B, HepG2, SMMC-7721 and Huh-7 cells, and normal hepatocyte L-02 cells. The relationship between APE1 expression and clinical pathological characteristics of HCC was statistically analyzed. APE1 shRNA vector was constructed in Hep 3B cells to establish a stably transfected cell line, using Western blots to determine the interference efficiency. Cell proliferation activity was detected with MTT assays, while apoptosis was detected with the Annexin V-FITC/PI double-labeling technique. The expression of APE1 in HCC tissues and cells was significantly up-regulated, and its expression was significantly different from TNM staging and histopathological grading. Down-regulation of APE1 expression significantly reduced the proliferative activity and increased the apoptosis rate of Hep 3B cells. In conclusion, APE1 demonstrates cancer progression potential at the clinical, tissue and cell level. It provides a new idea and theoretical basis for APE1-based clinical diagnosis, prognosis determination and molecular targeted therapy in treatment of HCC.

Differential expression of APE1 in hepatocellular carcinoma and the effects on proliferation and apoptosis of cancer cells

Nosocomial infection is a common complication after abdominal oncology surgery. Aimed at finding its independent risk factors for prevention, all the patients who underwent abdominal oncology surgery were summarized from March 1(st), 2010 to March 1(st), 2013 from the oncology surgery department, Beijing Shijitan Hospital. The investigated variances were patients' information including admission number, sex, age, diabetes, diagnosis, length of stay, American society of anesthesiologists (ASA) grade, surgery time, number of drainage tubes. Comparisons were taken between the infected cases and non-infected cases for retrospective logistic regression analysis. 4 variances including diabetes, preoperative hospitalization time ≥ 6 days, surgery time ≥ 230 minutes, ASA grade ≥ III were found out to be related to nosocomial infection after surgery. The 4 variances mentioned above were risk factors for nosocomial infection after surgery.

Regression analysis of the risk factors for postoperative nosocomial infection in patients with abdominal tumors: experience from a large cancer centre in China.

The current study describes the technical details of and the clinical prognosis for the "China stitch", a novel technique for hand-sewn esophagojejunostomy in totally laparoscopic total gastrectomy. This study also explores the feasibility and safety of the technique. Clinical data of 20 patients with esophagogastric junction cancer in Beijing Shijitan Hospital, Capital Medical University from January 2017 to April 2018 were retrospectively analyzed. All 20 patients underwent esophagojejunostomy via a novel hand-sewn technique that uses traction to turn the left or right wall of the esophagus into an anterior wall. This avoids the difficulty of suturing the posterior wall. All patients were followed until June 2019. All 20 patients successfully underwent the procedure. The mean operating time was 216.5 ± 24.9 (176-254) min, the mean hand-sewn reconstruction time was 44.4 ± 9.4 (26-61) min, intraoperative bleeding was 141.2 ± 24.9 (130-160) mL, and the number of resected lymph nodes was 23 ± 8 (14-33). After surgery, there was one case of anastomotic leakage and one case of anastomotic stenosis, but both were alleviated with conservative treatment. The mean duration of follow-up was 15 (4-33) months. There was no significant difference in postoperative complications of and short-term oncologic prognosis for the 20 patients who underwent hand-sewn esophagojejunostomy and the 21 patients who underwent mechanical esophagojejunostomy during the same period. In conclusion, the "China stitch", a novel hand-sewn technique, is a cost-effective, safe, and reliable method for esophagojejunostomy in totally laparoscopic total gastrectomy.

Technical details of and prognosis for the "China stitch", a novel technique for totally laparoscopic hand-sewn esophagojejunostomy.

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Differential expression of APE1 in hepatocellular carcinoma and the effects on proliferation and apoptosis of cancer cells

Regression analysis of the risk factors for postoperative nosocomial infection in patients with abdominal tumors: experience from a large cancer centre in China.

Technical details of and prognosis for the "China stitch", a novel technique for totally laparoscopic hand-sewn esophagojejunostomy.