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DR5 Receptor Mediates Anoikis in Human Colorectal Carcinoma Cell Lines

Departments of ¹ Oncology and ² Surgery, Georgetown University Medical Center, Washington, District of Columbia; ³ Department of Medicine, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and ⁴ Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York

Requests for reprints: J. Milburn Jessup, Cancer Diagnosis Program, National Cancer Institute, 6040 EPN, 6130 Executive Boulevard, Rockville, MD 20892. Phone: 301-435-9010; Fax: 301-402-7819; E-mail: jessupj{at}mail.nih.gov.

Key Words: TRAIL-R2 • DR5 • anoikis • apoptosis • metastasis • caspases • caspase-8 • extrinsic pathway • caspase-3 • colorectal carcinoma

As human colorectal cancer (CRC) cells metastasize to distant sites, they are susceptible to detachment-induced cell death or anoikis — a form of apoptosis that occurs when anchorage-dependent CRC cells go into suspension. Our goal was to identify whether tumor necrosis factor receptor apoptosis-inducing ligand (TRAIL) receptors mediate anoikis in human CRC cells. First, we assessed whether caspases of the extrinsic (caspase-8) or intrinsic (caspase-9) death pathways were involved. Caspase-8 was cleaved during exposure to suspension culture in four CRC lines, and cell death was inhibited by caspase-3 and caspase-8 inhibitors but not by a caspase-9 inhibitor. Gene transcripts in macrophage inflammatory protein-101 (MIP-110), a weakly metastatic human CRC, were increased at least 2-fold for TRAIL-R2 (DR5) and TRAIL after 24 h of suspension culture compared with cells in monolayer culture. The increased expression of DR5 was confirmed at the protein level at 24 h, and exposure of MIP-101 cells to an antagonistic antibody to DR5 decreased caspase-8 activation. The antagonistic antibody to DR5 inhibited anoikis in four human CRC lines. Treatment with an antagonistic DR4 antibody or a neutralizing antibody to TRAIL ligand did not reduce anoikis consistently. Knockdown of DR5 or TRAIL also inhibited anoikis, whereas exogenous TRAIL or FasL did not consistently increase anoikis. In summary, DR5 receptor mediates death signals for anoikis in human CRC cells through the extrinsic apoptotic pathway. [Cancer Res 2008;68(3):909–17]