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      MAP17 (PDZKIP1) Expression Determines Sensitivity to the Proteasomal Inhibitor Bortezomib by Preventing Cytoprotective Autophagy and NFκB Activation in Breast Cancer.

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          Abstract

          MAP17 is a small nonglycosylated membrane protein that is overexpressed in a high percentage of carcinomas. High levels of MAP17 enhance the tumorigenic properties of tumor cells by increasing oxidative stress, which is dependent on Na(+)-coupled cotransport. Here, we show that MAP17 is associated with proteins involved in protein degradation and that proteasome inhibition induces autophagy. To analyze whether MAP17 could also alter this process, we used the proteasome inhibitor bortezomib (Velcade, PS-341), which is approved for the treatment of multiple myeloma and mantle cell lymphoma, although it has a high rate of resistance emergence and poor efficacy in solid tumors. We provide evidence that bortezomib induces a cytoprotective effect by activating autophagy and NFκB nuclear translocation, responses that are repressed in the presence of high levels of MAP17 both in vitro and in vivo. Indeed, patients with multiple myeloma treated with bortezomib showed higher response rates and a longer time to progression associated with increased levels of MAP17 expression. The MAP17-induced sensitivity to bortezomib is dependent on the oxidative status of the cells and the activity of Na(+)-coupled transporters because treatment with antioxidants or the inhibitor furosemide restores the cytoprotective activity induced by bortezomib. Therefore, bortezomib induces a prosurvival response through cytoprotective autophagy and NFκB nuclear translocation, which is repressed by high levels of MAP17. We propose that the levels of MAP17 could be used as a prognostic marker to predict the response to bortezomib in hematologic malignancies and in other tissues that are not commonly responsive to the drug.

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          Author and article information

          Journal
          Mol. Cancer Ther.
          Molecular cancer therapeutics
          American Association for Cancer Research (AACR)
          1538-8514
          1535-7163
          Jun 2015
          : 14
          : 6
          Affiliations
          [1 ] Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain.
          [2 ] Department of Genetics, University of Seville, Seville, Spain.
          [3 ] Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain. acarnero-ibis@us.es.
          Article
          1535-7163.MCT-14-1053
          10.1158/1535-7163.MCT-14-1053
          25837675

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