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Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma

NOBORIO-HATANO, K ; KIKUCHI, J ; OZAKI, K ; MORI, M ; NAGAI, T ; MUROI, K ; KANO, Y ; FURUKAWA, Y ; OZAWA, K ; TAKATOKU, M ; SHIMIZU, R ; WADA, T ; UEDA, M ; NOBUYOSHI, M ; OH, I ; SATO, K ; SUZUKI, T

Oncogene, 2009-01, Vol.28 (2), p.231-242 [Periódico revisado por pares]

Basingstoke: Nature Publishing Group

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Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma
Autor: NOBORIO-HATANO, K ; KIKUCHI, J ; OZAKI, K ; MORI, M ; NAGAI, T ; MUROI, K ; KANO, Y ; FURUKAWA, Y ; OZAWA, K ; TAKATOKU, M ; SHIMIZU, R ; WADA, T ; UEDA, M ; NOBUYOSHI, M ; OH, I ; SATO, K ; SUZUKI, T
Assuntos: Antibodies - pharmacology ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Biological and medical sciences ; Boronic Acids - pharmacology ; Bortezomib ; Cancer ; Care and treatment ; Causes of ; Cell adhesion ; Cell adhesion & migration ; Cell Adhesion - physiology ; Cell Adhesion Molecules - physiology ; Cell Line, Tumor - metabolism ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Chemotherapy ; Dexamethasone - pharmacology ; Dosage and administration ; Down-Regulation ; Doxorubicin - pharmacology ; Drug resistance ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - physiology ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Knockdown Techniques ; Genetic aspects ; Health aspects ; Hematologic and hematopoietic diseases ; Humans ; Immunodeficiencies. Immunoglobulinopathies ; Immunoglobulinopathies ; Immunopathology ; Integrin alpha Chains - biosynthesis ; Integrin alpha Chains - genetics ; Integrin alpha Chains - physiology ; Integrin alpha4 - biosynthesis ; Integrin alpha4 - genetics ; Integrin alpha4 - physiology ; Integrin alpha4beta1 - physiology ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Medical sciences ; Molecular and cellular biology ; Multiple myeloma ; Multiple Myeloma - drug therapy ; Multiple Myeloma - metabolism ; Neoplasm Proteins - biosynthesis ; Neoplasm Proteins - genetics ; Neoplasm Proteins - physiology ; Oncology ; Pyrazines - pharmacology ; Vincristine - pharmacology
É parte de: Oncogene, 2009-01, Vol.28 (2), p.231-242
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SourceType-Scholarly Journals-1
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Descrição: Multiple myeloma (MM) is incurable, mainly because of cell adhesion-mediated drug resistance (CAM-DR). In this study, we performed functional screening using short hairpin RNA (shRNA) to define the molecule(s) responsible for CAM-DR of MM. Using four bona fide myeloma cell lines (KHM-1B, KMS12-BM, RPMI8226 and U266) and primary myeloma cells, we identified CD29 (beta1-integrin), CD44, CD49d (alpha4-integrin, a subunit of VLA-4), CD54 (intercellular adhesion molecule-1 (ICAM-1)), CD138 (syndecan-1) and CD184 (CXC chemokine receptor-4 (CXCR4)) as major adhesion molecules expressed on MM. shRNA-mediated knockdown of CD49d but not CD44, CD54, CD138 and CD184 significantly reversed CAM-DR of myeloma cells to bortezomib, vincristine, doxorubicin and dexamethasone. Experiments using blocking antibodies yielded almost identical results. Bortezomib was relatively resistant to CAM-DR because of its ability to specifically downregulate CD49d expression. This property was unique to bortezomib and was not observed in other anti-myeloma drugs. Pretreatment with bortezomib was able to ameliorate CAM-DR of myeloma cells to vincristine and dexamethasone. These results suggest that VLA-4 plays a critical role in CAM-DR of MM cells. The combination of bortezomib with conventional anti-myeloma drugs may be effective in overcoming CAM-DR of MM.
Editor: Basingstoke: Nature Publishing Group
Idioma: Inglês

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Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma

NOBORIO-HATANO, K ; KIKUCHI, J ; OZAKI, K ; MORI, M ; NAGAI, T ; MUROI, K ; KANO, Y ; FURUKAWA, Y ; OZAWA, K ; TAKATOKU, M ; SHIMIZU, R ; WADA, T ; UEDA, M ; NOBUYOSHI, M ; OH, I ; SATO, K ; SUZUKI, T

Basingstoke: Nature Publishing Group

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