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Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells.

ABSTRACT: Chemoresistance remains a major obstacle to successful treatment of breast cancer. Although soluble tumor necrosis factor-? (sTNF-?) has been implicated in mediating drug-resistance in human cancers, whether transmembrane tumor necrosis factor-? (tmTNF-?) plays a role in chemoresistance remains unclear. Here we found that over 50% of studied patients expressed tmTNF-? at high levels in breast cancer tissues and tmTNF-? expression positively correlated with resistance to anthracycline chemotherapy. Alteration of tmTNF-? expression changed the sensitivity of primary human breast cancer cells and breast cancer cell lines to doxorubicin (DOX). Overexpression of N-terminal fragment (NTF) of tmTNF-?, a mutant form with intact intracellular domain of tmTNF-? to transmit reverse signals, induced DOX-resistance. Mechanistically, the tmTNF-?/NTF-ERK-GST-? axis and tmTNF-?/NTF-NF-?B-mediated anti-apoptotic functions were required for tmTNF-?-induced DOX-resistance. In a xenograft mouse model, the combination of tmTNF-? suppression with chemotherapy significantly enhanced the efficacy of DOX. Our data indicate that tmTNF-? mediates DOX-resistance through reverse signaling and targeting tmTNF-? may be beneficial for the treatment of DOX-resistant breast cancer.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC6013421 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells.

Zhang Zunyue Z Lin Guohong G Yan Yujing Y Li Xiang X Hu Yibing Y Wang Jing J Yin Bingjiao B Wu Yaqun Y Li Zhuoya Z Yang Xiang-Ping XP

Oncogene 20180321 25

Chemoresistance remains a major obstacle to successful treatment of breast cancer. Although soluble tumor necrosis factor-α (sTNF-α) has been implicated in mediating drug-resistance in human cancers, whether transmembrane tumor necrosis factor-α (tmTNF-α) plays a role in chemoresistance remains unclear. Here we found that over 50% of studied patients expressed tmTNF-α at high levels in breast cancer tissues and tmTNF-α expression positively correlated with resistance to anthracycline chemotherap ...[more]

PMID: 29559745

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Project description:BACKGROUND:Claudin-6 (CLDN6), a member of CLDN family and a key component of tight junction, has been reported to function as a tumor suppressor in breast cancer. However, whether CLDN6 plays any role in breast cancer chemoresistance remains unclear. In this study, we investigated the role of CLDN6 in the acquisition of chemoresistance in breast cancer cells. METHODS:We manipulated the expression of CLDN6 in MCF-7 and MCF-7/MDR cells with lv-CLDN6 and CLDN6-shRNA and investigated whether CLDN6 manipulation lead to different susceptibilities to several chemotherapeutic agents in these cells. The cytotoxicity of adriamycin (ADM), 5-fluorouracil (5-FU), and cisplatin (DDP) was tested by cck-8 assay. Cell death was determined by DAPI nuclear staining. The enzyme activity of glutanthione S-transferase-p1 (GSTP1) was detected by a GST activity kit. Then lv-GSTP1 and GSTP1-shRNA plasmids were constructed to investigate the potential of GSTP1 in regulating chemoresistance of breast cancer. The TP53-shRNA was adopted to explore the regulation mechanism of GSTP1. Finally, immunohistochemistry was used to explore the relationship between CLDN6 and GSTP1 expression in breast cancer tissues. RESULTS:Silencing CLDN6 increased the cytotoxicity of ADM, 5-FU, and DDP in MCF-7/MDR cells. Whereas overexpression of CLDN6 in MCF-7, the parental cell line of MCF-7/MDR expressing low level of CLDN6, increased the resistance to the above drugs. GSTP1 was upregulated in CLDN6-overexpressed MCF-7 cells. RNAi -mediated silencing of CLDN6 downregulated both GSTP1 expression and GST enzyme activity in MCF-7/MDR cells. Overexpresssion of GSTP1 in CLDN6 silenced MCF-7/MDR cells restored chemoresistance, whereas silencing GSTP1 reduced the chemoresistance due to ectopic overexpressed of CLDN6 in MCF-7 cells. These observations were also repeated in TNBC cells Hs578t. We further confirmed that CLDN6 interacted with p53 and promoted translocation of p53 from nucleus to cytoplasm, and both the expression and enzyme activity of GSTP1 were regulated by p53. Clinicopathologic analysis revealed that GSTP1 expression was positively associated with CLDN6 in human breast cancer samples. CONCLUSION:High expression of CLDN6 confers chemoresistance on breast cancer which is mediated by GSTP1, the activity of which is regulated by p53. Our findings provide a new insight into mechanisms and strategies to overcome chemoresistance in breast cancer.

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Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells.

Publications

Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells.

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