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D Rhamnose ?-hederin reverses chemoresistance of breast cancer cells by regulating exosome-mediated resistance transmission.

ABSTRACT: d Rhamnose ?-hederin (DR?-H), an active component extracted from the traditional Chinese medicinal plant Clematis ganpiniana, has been reported to be effective against breast cancer. Recent studies have also indicated that the isolated exosomes (D/exo) from docetaxel-resistant breast cancer cells MCF-7 (MCF-7/Doc) were associated with resistance transmission by delivering genetic cargo. However, the relevance of D/exo during DR?-H exposure remains largely unclear. In the present work, exosomes were characterized by morphology and size distribution. We reinforced the significant role of D/exo in spreading chemoresistance from MCF-7/Doc to recipient sensitive cells after absorption and internalization. DR?-H could reduce the formation and release of D/exo. Next, we demonstrated that DR?-H was able to reverse docetaxel resistance and that D/exo was responsible for DR?-H-mediated resistance reversal. We also found that DR?-H could decrease the expressions of several most abundant miRNAs (miR-16, miR-23a, miR-24, miR-26a, and miR-27a) transported by D/exo. Target gene prediction and pathway analysis showed the involvement of these selected miRNAs in pathways related to treatment failure. Our results suggested that DR?-H could reduce D/exo secretion from MCF-7/Doc cells and induce the reduction in resistance transmission via D/exo.

SUBMITTER: Chen WX

PROVIDER: S-EPMC6165836 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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d Rhamnose β-hederin reverses chemoresistance of breast cancer cells by regulating exosome-mediated resistance transmission.

Chen Wei-Xian WX Xu Ling-Yun LY Qian Qi Q He Xiao X Peng Wen-Ting WT Fan Wen-Qiang WQ Zhu Yu-Lan YL Tang Jin-Hai JH Cheng Lin L

Bioscience reports 20180928 5

d Rhamnose β-hederin (DRβ-H), an active component extracted from the traditional Chinese medicinal plant <i>Clematis ganpiniana</i>, has been reported to be effective against breast cancer. Recent studies have also indicated that the isolated exosomes (D/exo) from docetaxel-resistant breast cancer cells MCF-7 (MCF-7/Doc) were associated with resistance transmission by delivering genetic cargo. However, the relevance of D/exo during DRβ-H exposure remains largely unclear. In the present work, exo ...[more]

PMID: 30061173

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Project description:BackgroundTamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance.MethodsMTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth.ResultsMTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression.ConclusionsOur results suggested that c-Cbl can reverse tamoxifen resistance in HER2-overexpressing breast cancer cells by inhibiting the formation of the ER-c-Src-HER2 complex.

Dataset Information

D Rhamnose ?-hederin reverses chemoresistance of breast cancer cells by regulating exosome-mediated resistance transmission.

Publications

d Rhamnose β-hederin reverses chemoresistance of breast cancer cells by regulating exosome-mediated resistance transmission.

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