Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma.
Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1alpha (Hif-1alpha) expression in MM cells, which is associated with oncogenic c-Myc. A drug screen for anti-MM agents that decrease Hif-1alpha and c-Myc levels identified a variety of compounds, including bortezomib, lenalidomide, enzastaurin, and adaphostin. Functionally, based on transient knockdowns and overexpression, our data delineate a c-Myc/Hif-1alpha-dependent pathway mediating vascular endothelial growth factor production and secretion. The antiangiogenic activity of our tool compound, adaphostin, was subsequently shown in a zebrafish model and translated into a preclinical in vitro and in vivo model of MM in the bone marrow milieu. Our data, therefore, identify Hif-1alpha as a novel molecular target in MM and add another facet to anti-MM drug activity.
Zhang
Jing
J
Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Boston, MA 02115, USA.
Sattler
Martin
M
Tonon
Giovanni
G
Grabher
Clemens
C
Lababidi
Samir
S
Zimmerhackl
Alexander
A
Raab
Marc S
MS
Vallet
Sonia
S
Zhou
Yiming
Y
Cartron
Marie-Astrid
MA
Hideshima
Teru
T
Tai
Yu-Tzu
YT
Chauhan
Dharminder
D
Anderson
Kenneth C
KC
Podar
Klaus
K
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000098:blood supply* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D006873:Hydroquinones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C404397:NSC 680410; D016271:Proto-Oncogene Proteins c-myc; D042461:Vascular Endothelial Growth Factor A; D000218:Adamantane