Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma.
Proteasome inhibitor PS-341 is one of the most promising novel agents against multiple myeloma (MM). We have previously shown that PS-341 inhibits IL-6 triggered phosphorylation of extracellular signal-regulated kinases (ERK) 1/2 (also known as p42/44 mitogen-activated protein kinases) in MM cells. In this study, we further examined whether clinically achievable concentrations of PS-341 could inhibit IL-6 triggered signaling cascades in MM. We found that PS-341 inhibited not only ERK, but also signal transducers and activators of transcription (STAT) 3 as well as Akt phosphorylation. Since gp130 (CD130) dimerizes and is phosphorylated after IL-6 binding to gp80 (IL-6 receptor), we hypothesized that gp130 could be involved in PS-341-induced blockade of signaling cascades mediating MM cell growth, survival, and drug resistance in the bone marrow (BM) microenvironment. In this study, we first demonstrate that PS-341 induces downregulation of gp130 in a time- and dose-dependent manner in vitro, prior to MM cell death. Conversely, downregulation of gp130 is completely abrogated by the pan-caspase inhibitor Z-VAD-FMK, suggesting that downregulation of gp130 is mediated via caspase activation. Z-VAD-FMK also abrogates the inhibitory effect of PS-341 on IL-6-triggered signaling cascades. Importantly, we demonstrate that phosphorylation of ERK, STAT3, and Akt in MM.1S cells induced by either exogenous IL-6 or by binding of MM cells to BM stromal cells is abrogated by PS-341. These studies, therefore, define another novel mechanism whereby PS-341 can overcome the growth and survival advantage in MM cells conferred by the BM milieu. Importantly, this effect on cytokine-induced gp130 signaling cascades may account, at least in part, for the remarkable preclinical sensitivity and clinical responses achieved in MM with PS-341 treatment.
Hideshima
Teru
T
Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Jerome Lipper Multiple Myeloma Center, 44 Binney Street, Boston, MA 02155, USA.
Chauhan
Dharminder
D
Hayashi
Toshiaki
T
Akiyama
Masaharu
M
Mitsiades
Nicholas
N
Mitsiades
Constantine
C
Podar
Klaus
K
Munshi
Nikhil C
NC
Richardson
Paul G
PG
Anderson
Kenneth C
KC
D001897:Boronic Acids / Q000378:metabolism*; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D058966:Contactins; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D001897:Boronic Acids; D058966:Contactins; D015850:Interleukin-6; D009097:Multienzyme Complexes; D019006:Neural Cell Adhesion Molecules; D011719:Pyrazines; D000069286:Bortezomib; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex