The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia.
Waldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma. We demonstrate up-regulated Akt activity in WM, and that Akt down-regulation by Akt knockdown and the inhibitor perifosine leads to significant inhibition of proliferation and induction of apoptosis in WM cells in vitro, but not in normal donor peripheral blood and hematopoietic progenitors. Importantly, down-regulation of Akt induced cytotoxicity of WM cells in the bone marrow microenvironment (BMM) context. Perifosine induced significant reduction in WM tumor growth in vivo in a subcutaneous xenograft model through inhibition of Akt phosphorylation and downstream targets. We also demonstrated that Akt pathway down-regulation inhibited migration and adhesion in vitro and homing of WM tumor cells to the BMM in vivo. Proteomic analysis identified other signaling pathways modulated by perifosine, such as activation of ERK MAPK pathway, which induces survival of tumor cells. Interestingly, MEK inhibitor significantly enhanced perifosine-induced cytotoxicity in WM cells. Using Akt knockdown experiments and specific Akt and PI3K inhibitors, we demonstrated that ERK activation is through a direct effect, rather than feedback activation, of perifosine upstream ERK pathway. These results provide understanding of biological effects of Akt pathway in WM and provide the framework for clinical evaluation of perifosine in WM patients.
Leleu
Xavier
X
Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Jia
Xiaoying
X
Runnels
Judith
J
Ngo
Hai T
HT
Moreau
Anne-Sophie
AS
Farag
Mena
M
Spencer
Joel A
JA
Pitsillides
Costas M
CM
Hatjiharissi
Evdoxia
E
Roccaro
Aldo
A
O'Sullivan
Garrett
G
McMillin
Douglas W
DW
Moreno
Daisy
D
Kiziltepe
Tanyel
T
Carrasco
Ruben
R
Treon
Steven P
SP
Hideshima
Teru
T
Anderson
Kenneth C
KC
Lin
Charles P
CP
Ghobrial
Irene M
IM
D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002470:Cell Survival; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D008258:Waldenstrom Macroglobulinemia / Q000473:pathology*
D010767:Phosphorylcholine; C105905:perifosine; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases