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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 The Sidney Kimmel Cancer Center, 2 The Torrey Pines Institute for Molecular Studies, 3 AntiCancer, Inc., 4 Department of Surgery, University of California, San Diego, California and 5 The Burnham Institute, La Jolla, California
Requests for reprints: Gennadi V. Glinsky, Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121. Phone: 858-450-5990; Fax: 858-623-2740; E-mail: gglinsky{at}skcc.org.
Survival in lymph or blood is an essential prerequisite for metastasis of carcinoma cells to distant organs. Recently, we reported isolation and initial biological characterization of circulating metastatic cells in a fluorescent, orthotopic, metastatic nude-mouse model of human prostate cancer. Here we show that the metastatic human prostate carcinoma cells selected for survival in the circulation have increased resistance to anoikis, which is apoptosis induced by cell detachment. Using gene silencing and gene transfer techniques, we show that increased expression of the apoptosis inhibitory protein XIAP contributes to anoikis resistance of the circulating metastatic human prostate carcinoma cells. We also provide initial preclinical data on the antimetastatic efficacy of recently discovered small-molecule antagonists of XIAP.
Key Words: prostate cancer • metastasis • apoptosis • XIAP • orthotopic implantation • small-molecule inhibitors
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