Ectopic cyclin D1 overexpression increases chemosensitivity but not cell proliferation in multiple myeloma.
We established a myeloma cell line (RPMI8226) with cyclin D1 overexpression in which the transfected cyclin D1 gene was stably expressed. D1 transfectants showed down-regulation of cyclin D2. Cell proliferation analysis did not show any differences among RPMI8226, mock control, and D1 transfectants. The number of S-phase cells increased while the number of G0/G1- and G2/M-phase cells decreased in D1 transfectants, which indicates a prolonged S-phase caused by cyclin D1 transfection. A decreased number of G2/M-phase cells was also detected in myeloma cells of patients with translocation t(11;14)(q13;q32). Western blot analysis revealed an increase in the hyperphosphorylated form of retinoblastoma (Rb) protein in D1 transfectants; however, the expression of p53, p16, Bax, Bad, Bcl-2, and Mcl-1 did not significantly change. Treatment with anti-myeloma drugs (melphalan, dexamethasone, bortezomib and immunomodulatory compounds) induced apoptosis earlier in D1 transfectants compared with RPMI8226 and mock control via the activation of both caspase-8 and -9. However, we could not detect a relationship between cyclin D1 expression and the response to treatment with VAD and bortezomib. Therefore, we assume that high sensitivity to anti-myeloma drugs depends on the duration of the S-phase, but a clinical response might depend on the number of myeloma cells with cyclin D1 overexpression.
Kuroda
Yoshiaki
Y
Department of Hematology and Oncology, RIRBM, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan.
Sakai
Akira
A
Tsuyama
Naohiro
N
Katayama
Yuta
Y
Munemasa
Shoso
S
Asaoku
Hideki
H
Okikawa
Yoshiko
Y
Nakaju
Nanae
N
Mizuno
Mami
M
Ogawa
Katsunari
K
Nishisaka
Takashi
T
Matsui
Hirotaka
H
Tanaka
Hideo
H
Kimura
Akiro
A
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D056742:Cyclin D2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011719:Pyrazines / Q000627:therapeutic use; D016160:Retinoblastoma Protein / Q000378:metabolism; D013792:Thalidomide / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D014750:Vincristine / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001897:Boronic Acids; C530104:CCND1 protein, human; C080336:CCND2 protein, human; C436291:CDKN1B protein, human; D056742:Cyclin D2; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D011719:Pyrazines; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013792:Thalidomide; D014750:Vincristine; D000069286:Bortezomib; D003907:Dexamethasone; D008558:Melphalan