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A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.

ABSTRACT: 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.

SUBMITTER: Ren B

PROVIDER: S-EPMC2981788 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.

Ren Bin B Song Keli K Parangi Sareh S Jin Taiguang T Ye Min M Humphreys Robin R Duquette Mark M Zhang Xuefeng X Benhaga Nordine N Lawler Jack J Khosravi-Far Roya R

Cancer research 20090414 9

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 inhibi ...[more]

PMID: 19366809

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A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.

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A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.

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