Dataset Information

Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin.

ABSTRACT: This study explores the contributions of neutrophils to chemotherapeutic resistance and berberine-regulated cancer cell sensitivity to doxorubicin (DOX). In vitro experiments, continuous DOX treatment led to the shift of HL-60 cells to N2 neutrophils and thus induced chemotherapeutic resistance. The combination treatment with DOX and 2 µM berberine resulted in the differentiation of HL-60 cells toward N1 and therefore stimulated HL-60 cell immune clearance. Berberine increased reactive oxygen species (ROS) and decreased autophagy and therefore induced apoptosis in HL-60-N2 cells with morphological changes, but had no effect on cell viability in HL-60-N1 cells. The neutrophil-regulating efficacy of berberine was confirmed in the urethane-induced lung carcinogenic model and H22 liver cancer allograft model. Furthermore, we found that DOX-derived neutrophils had high levels of CD133 and CD309 surface expression, which prevented both chemotherapeutic sensitivity and immune rejection by self-expression of PD-L1 and surface expression of PD-1 receptor on T cells, whereas berberine could downregulate CD133 and CD309 surface expression. Finally, berberine-relevant targets and pathways were evaluated. This study first suggests an important role of berberine in regulating neutrophil phenotypes to maintain cancer cell sensitivity to DOX.

SUBMITTER: Zhang S

PROVIDER: S-EPMC7000449 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin.

Zhang Shuhui S Zhou Lin L Zhang Mengdi M Wang Yuehua Y Wang Mengqi M Du Jincheng J Gu Wenwen W Kui Fuguang F Li Jiahuan J Geng Shengnan S Du Gangjun G

Frontiers in pharmacology 20200129

This study explores the contributions of neutrophils to chemotherapeutic resistance and berberine-regulated cancer cell sensitivity to doxorubicin (DOX). <i>In vitro</i> experiments, continuous DOX treatment led to the shift of HL-60 cells to N2 neutrophils and thus induced chemotherapeutic resistance. The combination treatment with DOX and 2 µM berberine resulted in the differentiation of HL-60 cells toward N1 and therefore stimulated HL-60 cell immune clearance. Berberine increased reactive ox ...[more]

PMID: 32063859

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Project description:BACKGROUND:Pancreatic cancer (PC) is a highly aggressive disease, and the lethality of this disease stems from early metastatic dissemination where surgical removal cannot provide a cure. Improvement of the therapeutic outcome and overall survival of PC patients requires to understand the fundamental processes that lead to metastasis such as the gain of cellular migration ability. One such family of proteins, which are essential players of cellular migration, is Semaphorin. Previously, we have identified one of the Semaphorin family member, Semaphorin-5A (SEMA5A) to be involved in organ-specific homing during PC metastasis. We have also demonstrated that SEMA5A has a constitutive expression in PC cell lines derived from metastatic sites in comparison with low endogenous expression in the primary tumor-derived cell line. In this study, we examined whether constitutive SEMA5A expression in metastatic PC cells regulates tumor growth and metastatic potential. METHODS:We generated SEMA5A knockdown in T3M-4 and CD18/HPAF cells and assessed their phenotypes on in vitro motility, tumor growth, and metastatic progression. RESULTS:In contrary to our initial expectations, orthotopic injection of SEMA5A knockdown cells into nude mice resulted in a significant increase in both tumor burden and liver metastases in comparison with the Control cells. Similarly, we observed higher in vitro migratory potential with pronounced morphological changes associated with epithelial-mesenchymal transition (EMT), a decrease in the expression of epithelial marker E-cadherin (E-Cad), increase in the expression of mesenchymal markers N-cadherin (N-Cad) and Snail and the activation of the Wnt-signaling pathway in SEMA5A knockdown cells. Furthermore, re-establishing SEMA5A expression with a knockdown resistant mouse Sema5A in SEMA5A knockdown cells resulted in a reversion to the epithelial state (mesenchymal-epithelial transition; MET), as indicated by the rescue of E-Cad expression and a decrease in N-Cad and Snail expression. CONCLUSIONS:Collectively, our data suggest that SEMA5A expression maintains epithelial phenotype in the metastatic microenvironment.

Dataset Information

Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin.

Publications

Berberine Maintains the Neutrophil N1 Phenotype to Reverse Cancer Cell Resistance to Doxorubicin.

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