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MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner.

ABSTRACT: Chemoresistance contributes to cancer relapse and increased mortality in a variety of cancer types, raising a pressing need to better understand the underlying mechanism. MUC1 is abnormally overexpressed in numerous carcinomas and associated with poor prognosis. However, the functional significance of MUC1 in chemoresistance has not been fully elucidated. Here, we showed that MUC1 expression was considerably induced in cells that had acquired chemoresistance at both transcriptional and post-translational levels. Using gain- and loss-of function approaches, we demonstrated a critical role of MUC1 in induction of drug resistance. Through stimulation of EGFR activation and nuclear translocation, MUC1 increased the expression of ATP-binding cassette transporter B1 (ABCB1). Remarkably, targeted suppression of EGFR or ABCB1 by both shRNAs and inhibitors effectively reversed chemoresistance. Moreover, co-administration of the inhibitors of MUC1-EGFR-ABCB1 with paclitaxel significantly blocked not only tumor growth but also relapse in xenograft mouse model. Our data collectively support a model in which MUC1 induces acquired chemotherapy resistance by upregulating ABCB1 in an EGFR-dependent manner, providing a novel molecular basis of using the EGFR inhibitor in MUC1-positive cancers to prevent chemotherapy resistance.

SUBMITTER: Jin W

PROVIDER: S-EPMC5596566 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner.

Jin Wei W Liao Xiaodong X Lv Yaping Y Pang Zhi Z Wang Yuming Y Li Quanfu Q Liao Yahui Y Ye Qing Q Chen Guoqiang G Zhao Kewen K Huang Lei L

Cell death & disease 20170810 8

Chemoresistance contributes to cancer relapse and increased mortality in a variety of cancer types, raising a pressing need to better understand the underlying mechanism. MUC1 is abnormally overexpressed in numerous carcinomas and associated with poor prognosis. However, the functional significance of MUC1 in chemoresistance has not been fully elucidated. Here, we showed that MUC1 expression was considerably induced in cells that had acquired chemoresistance at both transcriptional and post-tran ...[more]

PMID: 28796259

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Project description:Tumor cycling hypoxia is now a well-recognized phenomenon in animal and human solid tumors. However, how tumor cycling hypoxia impacts chemotherapy is unclear. In the present study, we explored the impact and the mechanism of cycling hypoxia on tumor microenvironment-mediated chemoresistance. Hoechst 33342 staining and hypoxia-inducible factor-1 (HIF-1) activation labeling together with immunofluorescence imaging and fluorescence-activated cell sorting were used to isolate hypoxic tumor subpopulations from human glioblastoma xenografts. ABCB1 expression, P-glycoprotein function, and chemosensitivity in tumor cells derived from human glioblastoma xenografts or in vitro cycling hypoxic stress-treated glioblastoma cells were determined using Western blot analysis, drug accumulation and efflux assays, and MTT assay, respectively. ABCB1 expression and P-glycoprotein function were upregulated under cycling hypoxia in glioblastoma cells concomitant with decreased responses to doxorubicin and BCNU. However, ABCB1 knockdown inhibited these effects. Moreover, immunofluorescence imaging and flow cytometric analysis for ABCB1, HIF-1 activation, and Hoechst 3342 in glioblastoma revealed highly localized ABCB1 expression predominantly in potentially cycling hypoxic areas with HIF-1 activation and blood perfusion in the solid tumor microenvironment. The cycling hypoxic tumor cells derived from glioblastoma xenografts exhibited higher ABCB1 expression, P-glycoprotein function, and chemoresistance, compared with chronic hypoxic and normoxic cells. Tumor-bearing mice that received YC-1, an HIF-1α inhibitor, exhibited suppressed tumor microenvironment-induced ABCB1 induction and enhanced survival rate in BCNU chemotherapy. Cycling hypoxia plays a vital role in tumor microenvironment-mediated chemoresistance through the HIF-1-dependent induction of ABCB1. HIF-1 blockade before and concurrent with chemotherapy could suppress cycling hypoxia-induced chemoresistance.

Dataset Information

MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner.

Publications

MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner.

Similar Datasets

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