A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Ren, B; Song, K; Parangi, S; Jin, T; Ye, M; Humphreys, R; Duquette, M; Zhang, X; Benhaga, N; Lawler, J; Khosravi-Far, R
Published Date
- May 1, 2009
Published In
Volume / Issue
- 69 / 9
Start / End Page
- 3856 - 3865
PubMed ID
- 19366809
Pubmed Central ID
- PMC2981788
Electronic International Standard Serial Number (EISSN)
- 1538-7445
Digital Object Identifier (DOI)
- 10.1158/0008-5472.CAN-08-2940
Language
- eng
Conference Location
- United States