Simvastatin and downstream inhibitors circumvent constitutive and stromal cell-induced resistance to doxorubicin in IGHV unmutated CLL cells
| Autor: | Marta Robino, Valentina Griggio, Barbara Castella, Marco Ladetto, Ilaria Buondonno, Daniela Drandi, Mario Boccadoro, Ivana Campia, Massimo Massaia, Candida Vitale, Chiara Riganti, Patrizia Sciancalepore, Micol Maria Rigoni, Marta Coscia, Myriam Foglietta |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Simvastatin ATP Binding Cassette Transporter Subfamily B Stromal cell RHOA Cell Survival Chronic lymphocytic leukemia Blotting Western Immunoglobulin Variable Region Cell Line statins multidrug resistance Tumor Cells Cultured medicine Animals Humans Protein kinase B Aged Aged 80 and over Antibiotics Antineoplastic chronic lymphocytic leukemia mevalonate pathway biology Kinase Middle Aged Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Leukemia Lymphocytic Chronic B-Cell Coculture Techniques Drug Resistance Multiple Oncology Doxorubicin Mutation Immunology biology.protein Cancer research Female Mevalonate pathway Stromal Cells Signal transduction Immunoglobulin Heavy Chains IGHV@ Signal Transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | The immunoglobulin heavy-chain variable region (IGHV) mutational status is a strong determinant of remission duration in chronic lymphocytic leukemia (CLL). The aim of this work was to compare the multidrug resistance (MDR) signature of IGHV mutated and unmutated CLL cells, identifying biochemical and molecular targets potentially amenable to therapeutic intervention. We found that the mevalonate pathway-dependent Ras/ERK1–2 and RhoA/RhoA kinase signaling cascades, and the downstream HIF-1α/P-glycoprotein axis were more active in IGHV unmutated than in mutated cells, leading to a constitutive protection from doxorubicin-induced cytotoxicity. The constitutive MDR phenotype of IGHV unmutated cells was partially dependent on B cell receptor signaling, as shown by the inhibitory effect exerted by ibrutinib. Stromal cells further protected IGHV unmutated cells from doxorubicin by upregulating Ras/ERK1–2, RhoA/RhoA kinase, Akt, HIF-1α and P-glycoprotein activities. Mevalonate pathway inhibition with simvastatin abrogated these signaling pathways and reversed the resistance of IGHV unmutated cells to doxorubicin, also counteracting the protective effect exerted by stromal cells. Similar results were obtained via the targeted inhibition of the downstream molecules ERK1–2, RhoA kinase and HIF-1α. Therefore, targeting the mevalonate pathway and its downstream signaling cascades is a promising strategy to circumvent the MDR signature of IGHV unmutated CLL cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|