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

Published

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

  • 19366809

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