A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR. Cancer Res 2009 May 01;69(9):3856-65
Date
04/16/2009Pubmed ID
19366809Pubmed Central ID
PMC2981788DOI
10.1158/0008-5472.CAN-08-2940Scopus ID
2-s2.0-65949084271 (requires institutional sign-in at Scopus site) 46 CitationsAbstract
As tumor development relies on a coordination of angiogenesis and tumor growth, an efficient antitumor strategy should target both the tumor and its associated vessels. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner. Additionally, thrombospondin-1, a naturally occurring inhibitor of angiogenesis, and a recombinant protein containing functional domains of thrombospondin-1, 3TSR, have been shown to be necessary and sufficient to inhibit tumor angiogenesis. Here, we show that a combination of a TRAIL receptor 2 agonist antibody, Lexatumumab, and 3TSR results in a significantly enhanced and durable tumor inhibition. We further observed that 3TSR induces apoptosis in primary endothelial cells by up-regulating the expression of TRAIL receptors 1 and 2 in a CD36 and Jun NH(2)-terminal kinase-dependent manner leading to the activation of both intrinsic and extrinsic apoptotic machineries. The modulation of these pathways is critical for 3TSR-induced apoptosis as disrupting either via specific inhibitors reduced apoptosis. Moreover, 3TSR attenuates the Akt survival pathway. These studies indicate that 3TSR plays a critical role in regulating the proapoptotic signaling pathways that control growth and death in endothelial cells and that a combination of TRAIL and 3TSR acts as a double hit against tumor and tumor-associated vessels.
Author List
Ren B, Song K, Parangi S, Jin T, Ye M, Humphreys R, Duquette M, Zhang X, Benhaga N, Lawler J, Khosravi-Far RMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Caspase 3
Caspase 8
Cells, Cultured
Colonic Neoplasms
Endothelial Cells
Enzyme Activation
Female
HCT116 Cells
Humans
MAP Kinase Kinase 4
Mice
Mice, Nude
Neovascularization, Pathologic
Peptide Fragments
Receptors, TNF-Related Apoptosis-Inducing Ligand
Recombinant Proteins
TNF-Related Apoptosis-Inducing Ligand
Thrombospondins
Xenograft Model Antitumor Assays
