23
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Src/STAT3-dependent heme oxygenase-1 induction mediates chemoresistance of breast cancer cells to doxorubicin by promoting autophagy

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Chemotherapeutic resistance in breast cancer, whether acquired or intrinsic, remains a major clinical obstacle. Thus, increasing tumor cell sensitivity to chemotherapeutic agents will be helpful in improving the clinical management of breast cancer. In the present study, we found an induction of HO-1 expression in doxorubicin (DOX)-treated MDA-MB-231 human breast adenocarcinoma cells, which showed insensitivity to DOX treatment. Knockdown HO-1 expression dramatically upregulated the incidence of MDA-MB-231 cell death under DOX treatment, indicating that HO-1 functions as a critical contributor to drug resistance in MDA-MB-231 cells. We further observed that DOX exposure induced a cytoprotective autophagic flux in MDA-MB-231 cells, which was dependent on HO-1 induction. Moreover, upregulation of HO-1 expression required the activation of both signal transducer and activator of transcription (STAT)3 and its upstream regulator, protein kinase Src. Abrogating Src/STAT3 pathway activation attenuated HO-1 and autophagy induction, thus increasing the chemosensitivity of MDA-MB-231 cells. Therefore, we conclude that Src/STAT3-dependent HO-1 induction protects MDA-MB-231 breast cancer cells from DOX-induced death through promoting autophagy. In the following study, we further demonstrated the contribution of Src/STAT3/HO-1/autophagy pathway activation to DOX resistance in another breast cancer cell line, MDA-MB-468, which bears a similar phenotype to MDA-MB-231 cells. Therefore, activation of Src/STAT3/HO-1/autophagy signaling pathway might play a general role in protecting certain subtypes of breast cancer cells from DOX-induced cytotoxicity. Targeting this signaling event may provide a potential approach for overcoming DOX resistance in breast cancer therapeutics.

          Related collections

          Most cited references40

          • Record: found
          • Abstract: found
          • Article: not found

          Autophagy is activated for cell survival after endoplasmic reticulum stress.

          Eukaryotic cells deal with accumulation of unfolded proteins in the endoplasmic reticulum (ER) by the unfolded protein response, involving the induction of molecular chaperones, translational attenuation, and ER-associated degradation, to prevent cell death. Here, we found that the autophagy system is activated as a novel signaling pathway in response to ER stress. Treatment of SK-N-SH neuroblastoma cells with ER stressors markedly induced the formation of autophagosomes, which were recognized at the ultrastructural level. The formation of green fluorescent protein (GFP)-LC3-labeled structures (GFP-LC3 "dots"), representing autophagosomes, was extensively induced in cells exposed to ER stress with conversion from LC3-I to LC3-II. In IRE1-deficient cells or cells treated with c-Jun N-terminal kinase (JNK) inhibitor, the autophagy induced by ER stress was inhibited, indicating that the IRE1-JNK pathway is required for autophagy activation after ER stress. In contrast, PERK-deficient cells and ATF6 knockdown cells showed that autophagy was induced after ER stress in a manner similar to the wild-type cells. Disturbance of autophagy rendered cells vulnerable to ER stress, suggesting that autophagy plays important roles in cell survival after ER stress.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The JAK2/STAT3 signaling pathway is required for growth of CD44⁺CD24⁻ stem cell-like breast cancer cells in human tumors.

            Intratumor heterogeneity is a major clinical problem because tumor cell subtypes display variable sensitivity to therapeutics and may play different roles in progression. We previously characterized 2 cell populations in human breast tumors with distinct properties: CD44+CD24- cells that have stem cell-like characteristics, and CD44-CD24+ cells that resemble more differentiated breast cancer cells. Here we identified 15 genes required for cell growth or proliferation in CD44+CD24- human breast cancer cells in a large-scale loss-of-function screen and found that inhibition of several of these (IL6, PTGIS, HAS1, CXCL3, and PFKFB3) reduced Stat3 activation. We found that the IL-6/JAK2/Stat3 pathway was preferentially active in CD44+CD24- breast cancer cells compared with other tumor cell types, and inhibition of JAK2 decreased their number and blocked growth of xenografts. Our results highlight the differences between distinct breast cancer cell types and identify targets such as JAK2 and Stat3 that may lead to more specific and effective breast cancer therapies.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential.

              Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. Induction of HO-1 protects against the cytotoxicity of oxidative stress and apoptotic cell death. More recently, HO-1 has been recognized to have major immunomodulatory and anti-inflammatory properties, which have been demonstrated in HO-1 knockout mice and a human case of genetic HO-1 deficiency. Beneficial protective effects of HO-1 in inflammation are not only mediated via enzymatic degradation of proinflammatory free heme, but also via production of the anti-inflammatory compounds bilirubin and carbon monoxide. The immunomodulatory role of HO-1 is associated with its cell type-specific functions in myeloid cells (eg. macrophages and monocytes) and in endothelial cells, as both cell types are crucially involved in the regulation of inflammatory responses. This review covers the molecular mechanisms and signaling pathways that are involved in HO-1 gene expression. In particular, it is discussed how redox-dependent transcriptional activators such as NF-E2 related factor 2 (Nrf2), NF-κB and AP-1 along with the transcription repressor BTB and CNC homologue 1 (Bach1) control the inducible HO-1 gene expression. The role of central pro- and anti-inflammatory cellular signaling cascades including p38 MAPK and phosphatidylinositol-3 kinase (PI3K)/Akt in HO-1 regulation is highlighted. Finally, emerging strategies that apply targeted pharmacological induction of HO-1 for therapeutic interventions in inflammatory conditions are summarized. Copyright © 2010 Elsevier Inc. All rights reserved.
                Bookmark

                Author and article information

                Journal
                Cancer Sci
                Cancer Sci
                cas
                Cancer Science
                John Wiley & Sons, Ltd (Chichester, UK )
                1347-9032
                1349-7006
                August 2015
                14 July 2015
                : 106
                : 8
                : 1023-1032
                Affiliations
                [1 ]Department of Stress Medicine, Beijing Institute of Basic Medical Sciences Beijing, China
                [2 ]Department of Breast Surgery, Guangxi Medical University Tumor Hospital Nanning, China
                [3 ]Laboratory of Cellular and Molecular Immunology, School of Medicine, Henan University Kaifeng, China
                [4 ]Department of New Drug Screening Center, China Pharmaceutical University Nanjing, China
                Author notes
                Correspondence Lun Song, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, China., Tel: 86-10-68210077 ext. 930320; Fax: 86-10-68213039;, E-mail: lunsong@ 123456yahoo.com , and, Changyuan Wei, Guangxi Medical University Tumor Hospital, 71 Hedi Road, Nanning 530021, China., Tel: 86-771-5332606; Fax: 86-771-5312000;, E-mail: weicy63@ 123456aliyun.com

                Funding InformationNational Natural Science Foundation of China; and National Key Research and Development Programs on Fundamental Sciences.

                Article
                10.1111/cas.12712
                4556392
                26041409
                ca959281-81ae-45db-8b5e-7a7491455f82
                © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 30 January 2015
                : 27 May 2015
                : 28 May 2015
                Categories
                Original Articles

                Oncology & Radiotherapy
                autophagy,chemoresistance,heme oxygenase-1,src,stat3
                Oncology & Radiotherapy
                autophagy, chemoresistance, heme oxygenase-1, src, stat3

                Comments

                Comment on this article