Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia.
Waldenström macroglobulinemia (WM) is an incurable low-grade B-cell lymphoma characterized by high protein turnover. We dissected the biologic role of the proteasome in WM using 2 proteasome inhibitors, NPI-0052 and bortezomib. We found that NPI-0052 inhibited proliferation and induced apoptosis in WM cells, and that the combination of NPI-0052 and bortezomib induced synergistic cytotoxicity in WM cells, leading to inhibition of nuclear translocation of p65NF-kappaB and synergistic induction of caspases-3, -8, and -9 and PARP cleavage. These 2 agents inhibited the canonical and noncanonical NF-kappaB pathways and acted synergistically through their differential effect on Akt activity and on chymotrypsin-like, caspaselike, and trypsinlike activities of the proteasome. We demonstrated that NPI-0052-induced cytotoxicity was completely abrogated in an Akt knockdown cell line, indicating that its major activity is mediated through the Akt pathway. Moreover, we demonstrated that NPI-0052 and bortezomib inhibited migration and adhesion in vitro and homing of WM cells in vivo, and overcame resistance induced by mesenchymal cells or by the addition of interleukin-6 in a coculture in vitro system. Theses studies enhance our understanding of the biologic role of the proteasome pathway in WM, and provide the preclinical basis for clinical trials of combinations of proteasome inhibitors in WM.
Roccaro
Aldo M
AM
Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA.
Leleu
Xavier
X
Sacco
Antonio
A
Jia
Xiaoying
X
Melhem
Molly
M
Moreau
Anne-Sophie
AS
Ngo
Hai T
HT
Runnels
Judith
J
Azab
Abdelkareem
A
Azab
Feda
F
Burwick
Nicholas
N
Farag
Mena
M
Treon
Steven P
SP
Palladino
Michael A
MA
Hideshima
Teru
T
Chauhan
Dharminder
D
Anderson
Kenneth C
KC
Ghobrial
Irene M
IM
D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D004357:Drug Synergism; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D001897:Boronic Acids; D007783:Lactones; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011758:Pyrroles; D000069286:Bortezomib; C475865:marizomib