4
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Interleukin-6 mediates resistance to PI3K-pathway–targeted therapy in lymphoma

      research-article
      1 , 1 , 2 , , 3 ,
      BMC Cancer
      BioMed Central
      Lymphoma, PI3K, Copanlisib, Duvelisib, Drug resistance, IL-6

      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

          Background

          The phosphoinositol 3-kinase (PI3K) pathway is associated with poor prognosis of hematologic malignancies, providing a strong rationale for the use of PI3K inhibitors in the treatment of malignant lymphoma. However, development of resistance limits the use of PI3K inhibitors in lymphoma patients.

          Methods

          We established copanlisib (pan-PI3K inhibitor)-resistant B-cell lymphoma and duvelisib (PI3Kδ and -γ inhibitor)-resistant T-cell lymphoma cell lines. The cytokine array and the phospho-kinase array were used to identify up-regulated proteins in the resistant cells. Cytokine expression and phospho-kinase levels were examined by ELISA and Western blot analysis, respectively. Cell proliferation capabilities were measured by using CCK-8 kit and colony formation assay. The effects of inhibitors on apoptosis were detected using an Annexin V-FITC Apoptosis Detection Kit and a flow cytometry system. The underlying mechanisms were studied by transfecting recombinant plasmids or siRNA into lymphoma cell lines. Cells were transiently transfected using the Amaxa electroporation system. We evaluated the effects of PI3K inhibitor alone and in combination with JAK inhibitor (BSK805) on lymphoma proliferation and signaling pathway activation.

          Results

          Cytokine arrays revealed upregulation of interleukin (IL)-6 in both copanlisib- and duvelisib-resistant cell lines. Phosphorylated STAT5, AKT, p70S6K and MAPK were increased in copanlisib-resistant B-cell lymphoma cells, whereas phosphorylated STAT3 and NF-κB were increased in duvelisib-resistant T cell lymphoma cells. Conversely, depletion of IL-6 sensitized both resistant cell lines, and led to downregulation of phosphorylated STAT3 and STAT5 in copanlisib- and duvelisib-resistant cells, respectively. Moreover, combined treatment with a JAK inhibitor (BSK805) and a PI3K inhibitor circumvented the acquired resistance to PI3K inhibitors in lymphoma, and concurrent inhibition of the activated pathways produced combined effects.

          Conclusions

          IL-6–induced STAT3 or STAT5 activation is a critical mechanism underlying PI3K inhibitor resistance in lymphoma, supporting the utility of IL-6 as an effective biomarker to predict therapeutic response to PI3K inhibitors.

          Electronic supplementary material

          The online version of this article (10.1186/s12885-019-6057-7) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references26

          • Record: found
          • Abstract: found
          • Article: found

          Non-Hodgkin lymphoma.

          Lymphomas are solid tumours of the immune system. Hodgkin's lymphoma accounts for about 10% of all lymphomas, and the remaining 90% are referred to as non-Hodgkin lymphoma. Non-Hodgkin lymphomas have a wide range of histological appearances and clinical features at presentation, which can make diagnosis difficult. Lymphomas are not rare, and most physicians, irrespective of their specialty, will probably have come across a patient with lymphoma. Timely diagnosis is important because effective, and often curative, therapies are available for many subtypes. In this Seminar we discuss advances in the understanding of the biology of these malignancies and new, available treatments. Copyright © 2012 Elsevier Ltd. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex.

            The macrophage migration inhibitory factor (MIF) receptor (CD74) was cloned recently, but the signaling mechanism is not evident. We hypothesized that signaling requires an additional molecule such as CD44, which activates nonreceptor tyrosine kinases. We utilized the CD74- and CD44-deficient COS-7/M6 cell to create stable transfectants expressing CD74, CD44, and a truncated CD44 lacking its intracytoplasmic signaling domain. CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44. MIF binding was associated with the serine phosphorylation of CD74 and CD44. Investigations that used siRNA or kinase inhibitors indicate that MIF-induced ERK1 and ERK2 activation through CD44 required the Src tyrosine kinase. Studies of CD74, CD44, and CD74-CD44 transformants and corresponding mutant cells showed that CD74 and CD44 were necessary for MIF protection from apoptosis. These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB.

              We have identified a novel mitogen- and stress-activated protein kinase (MSK1) that contains two protein kinase domains in a single polypeptide. MSK1 is activated in vitro by MAPK2/ERK2 or SAPK2/p38. Endogenous MSK1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to UV radiation, and oxidative and chemical stress. The activation of MSK1 by growth factors/phorbol esters is prevented by PD 98059, which suppresses activation of the MAPK cascade, while the activation of MSK1 by stress stimuli is prevented by SB 203580, a specific inhibitor of SAPK2/p38. In HeLa, PC12 and SK-N-MC cells, PD 98059 and SB 203580 are both required to suppress the activation of MSK1 by TNF, NGF and FGF, respectively, because these agonists activate both the MAPK/ERK and SAPK2/p38 cascades. MSK1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates CREB at Ser133 with a Km value far lower than PKA, MAPKAP-K1(p90Rsk) and MAPKAP-K2. The effects of SB 203580, PD 98059 and Ro 318220 on agonist-induced activation of CREB and ATF1 in four cell-lines mirror the effects of these inhibitors on MSK1 activation, and exclude a role for MAPKAP-K1 and MAPKAP-K2/3 in this process. These findings, together with other observations, suggest that MSK1 may mediate the growth-factor and stress-induced activation of CREB.
                Bookmark

                Author and article information

                Contributors
                +82 2 3410 6548 , wskimsmc@skku.edu
                +82 2 3410 3458 , cpark@skku.edu
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                10 October 2019
                10 October 2019
                2019
                : 19
                : 936
                Affiliations
                [1 ]ISNI 0000 0001 2181 989X, GRID grid.264381.a, Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, , Sungkyunkwan University, ; Seoul, 06351 Korea
                [2 ]ISNI 0000 0001 2181 989X, GRID grid.264381.a, Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, , Sungkyunkwan University School of Medicine, ; Seoul, 06351 Korea
                [3 ]ISNI 0000 0001 2181 989X, GRID grid.264381.a, Research Institute for Future Medicine, Samsung Medical Center, , Sungkyunkwan University School of Medicine, ; Seoul, 06351 Korea
                Article
                6057
                10.1186/s12885-019-6057-7
                6785854
                31601188
                25fe4b72-fc96-452b-93d4-33194a865abc
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 22 March 2019
                : 19 August 2019
                Funding
                Funded by: Basic Science Research Program through the National Research Foundation of Korea
                Award ID: 2018R1D1A1B07050170
                Award Recipient :
                Funded by: the Basic Science Research Program through the National Research Foundation of Korea
                Award ID: 2018R1D1A1B07044197
                Award Recipient :
                Funded by: the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology and the Korean Government
                Award ID: NRF-2018H1A2A1063095-Fostering Core Leaders of the Future Basic Science Program/Global Ph.D. Fellowship Program
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                lymphoma,pi3k,copanlisib,duvelisib,drug resistance,il-6
                Oncology & Radiotherapy
                lymphoma, pi3k, copanlisib, duvelisib, drug resistance, il-6

                Comments

                Comment on this article