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TopBP1 contributes to the chemoresistance in non-small cell lung cancer through upregulation of p53.

ABSTRACT: Resistance to chemotherapeutic drugs is a major obstacle in non-small cell lung cancer (NSCLC) therapy. The molecular determinants of NSCLC resistance to doxorubicin are unknown. In the present study, we investigated whether topoisomerase II? binding protein 1 (TopBP1) was involved in the chemoresistance to doxorubicin in NSCLC cancer. We found that p53-deficient lung cancer cells (NCI-H1299) displayed the greatest resistance to doxorubicin compared with NCI-H358, A549, and HCC827 cells with p53 expression. The expression of TopBP1 was significantly higher in NCI-H1299 cells than the other three tumor cell lines. In addition, TopBP1 knockdown with specific small interfering RNA in NCI-H1299 cells enhanced the doxorubicin chemosensitivity and decreased the expression of p53 in the presence of doxorubicin. After doxorubicin administration, co-immunoprecipitation assay showed that TopBP1 promoted the expression of p53 in NCI-H1299 cells. These results for the first time demonstrated that TopBP1 plays an important role in NSCLC chemoresistance via upregulation of p53. Therefore, inhibition of TopBP1, in combination with chemotherapy, may represent a novel strategy for the treatment of chemotherapy-resistant NSCLC.

SUBMITTER: Lv Y

PROVIDER: S-EPMC5042189 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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TopBP1 contributes to the chemoresistance in non-small cell lung cancer through upregulation of p53.

Lv Yinxiang Y Huo Yanan Y Yu Xican X Liu Rongrong R Zhang Shufen S Zheng Xiaoxiao X Zhang Xianning X

Drug design, development and therapy 20160923

Resistance to chemotherapeutic drugs is a major obstacle in non-small cell lung cancer (NSCLC) therapy. The molecular determinants of NSCLC resistance to doxorubicin are unknown. In the present study, we investigated whether topoisomerase IIβ binding protein 1 (TopBP1) was involved in the chemoresistance to doxorubicin in NSCLC cancer. We found that p53-deficient lung cancer cells (NCI-H1299) displayed the greatest resistance to doxorubicin compared with NCI-H358, A549, and HCC827 cells with p53 ...[more]

PMID: 27729767

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Project description:The highly refractory nature of non-small cell lung cancer (NSCLC) to chemotherapeutic drugs is an important factor resulting in its poor prognosis. Recent studies have revealed that tumour necrosis factor alpha-induced protein 8 (TNFAIP8) is involved in various biological and pathological processes of cells, but their underlying mechanisms in processes ranging from cancer development to drug resistance have not been fully elucidated.TNFAIP8 expression in clinical NSCLC samples was examined through immunohistochemistry (IHC). After adjusting for patients' characteristics with propensity score matching, Kaplan-Meier analysis and Cox regression analysis were performed for comparison of patients' survival according to the TNFAIP8 level. Lentiviral transfection with TNFAIP8-specific shRNAs was used to establish stable TNFAIP8 knockdown (TNFAIP8 KD) NCI-H460, A549 and cis-diamminedichloroplatinum II resistant A549 (A549/cDDP) cell lines. Cell proliferation and viability were assessed by CCK-8 assay. Cell cycle was examined by flow cytometry. Multiple pathways regulated by TNFAIP8 KD were revealed by microarray analysis.We found that high TNFAIP8 expression was associated with advanced pT stage, advanced pTNM stage, lymph node metastasis and unfavourable survival in NSCLC patients. TNFAIP8 shRNAs reduced in vitro cancer cell proliferation and in vivo tumor growth. Additionally, TNFAIP8 KD increased the sensitivity of NSCLC cells to cisplatin in vitro and in vivo. Conversely, up-regulation of TNFAIP8 promoted the?proliferation and?drug resistance to cisplatin?of NSCLC cells. TNFAIP8 influences cancer progression pathways involving the MDM2/p53 pathway. Indeed, we observed that TNFAIP8 KD mediated the MDM2 downregulation and the p53 ubiquitination, thereby decreasing the degradation of p53 protein. shRNA p53 reversed TNFAIP8 shRNA-mediated regulation of cell proliferation, cell cycle, cisplatin sensitivity, and expression levels of RAD51, a DNA repair gene.Our work uncovers a hitherto unappreciated role of TNFAIP8 in NSCLC proliferation and cisplatin chemoresistance that is mediated through the MDM2/p53 pathway. These findings might offer potential therapeutic targets for reversing cisplatin resistance in NSCLC patients with high TNFAIP8 expression.

Project description:Lung cancer is the most frequent cancer type and the leading cause of tumor-associated deaths worldwide. TP53 is an important tumor suppressor gene and is frequently inactivated in lung cancer. E3 ligases targeting p53, such as MDM2, are involved in the development of lung cancer. The E3 ligase HUWE1, which targets many tumor-associated proteins including p53, has been reported to be highly expressed in lung cancer; however, its role in lung tumorigenesis is unclear. Methods: The expression of HUWE1 and p53 in lung cancer cells was modulated and the phenotypes were assessed by performing soft agar colony forming assays, cell cycle analysis, BrdU incorporation assays, and xenograft tumor growth assays. The effect on tumorigenesis in genetically-engineered mice was also analyzed. The mechanism through which HUWE1 sustained lung cancer cell malignancy was confirmed by western blotting. HUWE1 expression in clinical lung cancer was identified by immunohistochemistry and validated by analyzing lung adenocarcinoma and lung squamous carcinoma samples from the Cancer Genome Atlas (TCGA) database. Finally, we assessed the association between HUWE1 expression and patient outcome using online survival analysis software including survival information from the caBIG, GEO, and TCGA database. Results: Inactivation of HUWE1 in a human lung cancer cell line inhibited proliferation, colony-forming capacity, and tumorigenicity. Mechanistically, this phenotype was driven by increased p53, which was due to attenuated proteasomal degradation by HUWE1. Up-regulation of p53 inhibited cancer cell malignancy, mainly through the induction of p21 expression and the down-regulation of HIF1?. Huwe1 deletion completely abolished the development of EGFRVIII-induced lung cancer in Huwe1 conditional knockout mice. Furthermore, survival analysis of lung cancer patients showed that increased HUWE1 expression is significantly associated with worse prognosis. Conclusion: Our data suggest that HUWE1 plays a critical role in lung cancer and that the HUWE1-p53 axis might be a potential target for lung cancer therapy.

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TopBP1 contributes to the chemoresistance in non-small cell lung cancer through upregulation of p53.

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TopBP1 contributes to the chemoresistance in non-small cell lung cancer through upregulation of p53.

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