Bortezomib overcomes cell-adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma.
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.
Noborio-Hatano
K
K
Division of Hematology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.
Kikuchi
J
J
Takatoku
M
M
Shimizu
R
R
Wada
T
T
Ueda
M
M
Nobuyoshi
M
M
Oh
I
I
Sato
K
K
Suzuki
T
T
Ozaki
K
K
Mori
M
M
Nagai
T
T
Muroi
K
K
Kano
Y
Y
Furukawa
Y
Y
Ozawa
K
K
D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology; D045744:Cell Line, Tumor / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D039001:Integrin alpha Chains / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D039441:Integrin alpha4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D039041:Integrin alpha4beta1 / Q000502:physiology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011719:Pyrazines / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D000906:Antibodies; D000970:Antineoplastic Agents; D001897:Boronic Acids; C063493:CDw49d; D015815:Cell Adhesion Molecules; D039001:Integrin alpha Chains; D039041:Integrin alpha4beta1; D009363:Neoplasm Proteins; D011719:Pyrazines; D039441:Integrin alpha4; D014750:Vincristine; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin