Down-regulation of CD9 by methylation decreased bortezomib sensitivity in multiple myeloma.
Bortezomib therapy has been proven successful for the treatment of relapsed and/or refractory multiple myeloma (MM). However, both intrinsic and acquired resistance has already been observed. In this study, we explored the relationship between CD9 expression and bortezomib sensitivity in MM. We found that down-regulation of CD9 by methylation decreased bortezomib sensitivity in multiple myeloma. CD9 expression obviously increased bortezomib sensitivity through inducing apoptosis, significantly inhibiting U266 cells' adhesion to HS-5 and primary bone marrow stromal cells, but increasing U266 cells' adhesion to fibronectin. CD9 expression also significantly inhibited U266 cell migration. The mechanisms may include: the endoplasmic reticulum stress pathway, cell adhesion related signaling pathway and osteoclast differentiation related signaling pathway. Combination therapy with de-methylation reagent 5-Aza-2-deoxycytidine may prove useful to the development of novel strategies for the treatment of bortezomib-resistant MM patients.
Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
Xiaotong
X
Hu
Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Han
H
Xuan
Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Huaping
H
Du
Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Hao
H
Jiang
Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
Jinwen
J
Huang
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D011719:Pyrazines / Q000494:pharmacology*; D060245:Tetraspanin 29 / Q000235:genetics*
D001897:Boronic Acids; D011719:Pyrazines; D060245:Tetraspanin 29; D000069286:Bortezomib; D000077209:Decitabine; D001374:Azacitidine