Tetraspanin CD82 drives Acute Myeloid Leukemia chemoresistance by modulating Protein Kinase C alpha and β1 integrin activation
| Autor: | Keith A. Lidke, Jennifer M. Gillette, Kristopher D. Marjon, Muskan Floren, Sebastian Restrepo Cruz, Christina M. Termini |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Adult Male Cancer Research Protein Kinase C-alpha Daunorubicin p38 mitogen-activated protein kinases HL-60 Cells Biology Kangai-1 Protein p38 Mitogen-Activated Protein Kinases Article 03 medical and health sciences 0302 clinical medicine Tetraspanin hemic and lymphatic diseases Genetics medicine Humans RNA-Seq Protein kinase A Molecular Biology Protein kinase C Aged Integrin beta1 Myeloid leukemia Middle Aged Gene Expression Regulation Neoplastic Leukemia Myeloid Acute 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Female CD82 medicine.drug |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | A principal challenge in treating acute myeloid leukemia (AML) is chemotherapy refractory disease. As such, there remains a critical need to identify key regulators of chemotherapy resistance in AML. In this study, we demonstrate that the membrane scaffold, CD82, contributes to the chemoresistant phenotype of AML. Using an RNA-seq approach, we identified the increased expression of the tetraspanin family member, CD82, in response to the chemotherapeutic, daunorubicin. Analysis of the TARGET and BEAT AML databases identifies a correlation between CD82 expression and overall survival of AML patients. Moreover, using a combination of cell lines and patient samples, we find that CD82 overexpression results in significantly reduced cell death in response to chemotherapy. Investigation of the mechanism by which CD82 promotes AML survival in response to chemotherapy identified a crucial role for enhanced protein kinase c alpha (PKCα) signaling and downstream activation of the β1 integrin. Additionally, analysis of β1 integrin clustering by super-resolution imaging demonstrates that CD82 expression promotes the formation of dense β1 integrin membrane clusters. Lastly, evaluation of survival signaling following daunorubicin treatment identified robust activation of p38 mitogen-activated protein kinase (MAPK) downstream of PKCα and β1 integrin signaling when CD82 is overexpressed. Together, these data propose a mechanism where CD82 promotes chemoresistance by increasing PKCα activation and downstream activation/clustering of β1 integrin, leading to AML cell survival via activation of p38 MAPK. These observations suggest that the CD82-PKCα signaling axis may be a potential therapeutic target for attenuating chemoresistance signaling in AML. |
| Databáze: | OpenAIRE |
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