Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells.
Multiple myeloma (MM) is a plasma cell malignancy that occurs mainly in bone marrow. As MM cells proliferate slowly, it would seem essential to find means of preventing their growth and accumulation inside bone marrow. The present study used an antisense strategy to elucidate the respective roles of Bcl-2, Bcl-x(L), and Mcl-1 proteins in myeloma cell survival. Each antisense oligonucleotide (ASO; Bcl-2, Bcl-x(L), or Mcl-1 ASO) introduced into human myeloma cell lines by electroporation induced a marked reduction in the level of the corresponding protein. Mcl-1 ASO triggers an important decrease of viability in all myeloma cell lines tested and in 2 primary myeloma cells, whereas neither Bcl-2 nor Bcl-x(L) ASO affected the viability of myeloma cells. The decrease of cell viability induced by Mcl-1 ASO treatment was associated with an induction of apoptosis that occurred through the disruption of mitochondrial membrane potential Delta Psi m and the activation of executioner caspase-3. Furthermore, we have shown that interleukin 6 cannot prevent the Mcl-1 ASO-induced apoptosis. Finally, although Bcl-2 ASO treatment alone has no effect, it can sensitize myeloma cell lines to dexamethasone (Dex), whereas Bcl-x(L) ASO in combination with Dex still had no effect. As MM remains an incurable disease despite intensive chemotherapy, these results suggest that Mcl-1 antisense strategy rather than Bcl-2 antisense strategy could be of considerable importance in the treatment of MM.
Derenne
Sophie
S
Institut National de la Santé et de la Recherche Médicale Unité 463 Institut de Biologie, Nantes, France.
Monia
Brett
B
Dean
Nicholas M
NM
Taylor
Jennifer K
JK
Rapp
Marie-Josée
MJ
Harousseau
Jean-Luc
JL
Bataille
Régis
R
Amiot
Martine
M
D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010954:Plasmacytoma / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein