Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells.
Akt mediates growth and drug resistance in multiple myeloma (MM) cells in the bone marrow (BM) microenvironment. We have shown that a novel Akt inhibitor Perifosine induces significant cytotoxicity in MM cells in the BM milieu. This study further delineated molecular mechanisms whereby Perifosine triggered cytotoxicity in MM cells. Neither the intensity of Jun NH(2)-terminal kinase phosphorylation nor caspase/poly (ADP-ribose) polymerase cleavage correlated with Perifosine-induced cytotoxicity in MM.1S, INA6, OPM1 and OPM2 MM cells. However, survivin, which regulates caspase-3 activity, was markedly downregulated by Perifosine treatment, without changes in other anti-apoptotic proteins. Downregulation of survivin by siRNA significantly inhibited OPM1 MM cell growth, confirming that survivin mediates MM cell survival. Perifosine significantly downregulated both function and protein expression of beta-catenin. Co-culture with BM stromal cells (BMSCs) upregulated both beta-catenin and survivin expression in MM cells, which was blocked by Perifosine. Importantly, Perifosine treatment also downregulated survivin expression in human MM cells grown in vivo in a severe combined immunodeficient mouse xenograft model. Finally, Perifosine inhibited bortezomib-induced upregulation of survivin, associated with enhanced cytotoxicity of combined bortezomib and Perifosine treatment. These preclinical studies provide the framework for clinical trials of bortezomib with Perifosine to improve patient outcome in MM.
Hideshima
Teru
T
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Catley
Laurence
L
Raje
Noopur
N
Chauhan
Dharminder
D
Podar
Klaus
K
Mitsiades
Constantine
C
Tai
Yu-Tzu
YT
Vallet
Sonia
S
Kiziltepe
Tanyel
T
Ocio
Enrique
E
Ikeda
Hiroshi
H
Okawa
Yutaka
Y
Hideshima
Hiromasa
H
Munshi
Nikhil C
NC
Yasui
Hiroshi
H
Richardson
Paul G
PG
Anderson
Kenneth C
KC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077022:Survivin; D014183:Transplantation, Heterologous
C107489:BIRC5 protein, human; D001897:Boronic Acids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; D000077022:Survivin; D010767:Phosphorylcholine; C105905:perifosine; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt