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Down-regulation of RAB6KIFL/KIF20A, a Kinesin Involved with Membrane Trafficking of Discs Large Homologue 5, Can Attenuate Growth of Pancreatic Cancer Cell

¹ Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; ² Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; and ³ Department of Gastroenterology and Hepatology, Kochi Medical School, Nankoku, Japan

Requests for reprints: Yusuke Nakamura, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5372; Fax: 81-3-5449-5433; E-mail: yusuke{at}ims.u-tokyo.ac.jp.

To identify novel molecular targets for treatment of pancreatic ductal adenocarcinoma (PDAC), we generated precise gene expression profiles of PDACs on a genome-wide cDNA microarray after populations of tumor cells were purified by laser microdissection. Through functional analysis of genes that were transactivated in PDACs, we identified RAB6KIFL as a candidate for development of drugs to treat PDACs at the molecular level. Knockdown of endogenous RAB6KIFL expression in PDAC cell lines by small interfering RNA drastically attenuated growth of those cells, suggesting an essential role for the gene product in maintaining viability of PDAC cells. RAB6KIFL belongs to the kinesin superfamily of motor proteins, which have critical functions in trafficking of molecules and organelles. Proteomics analyses using a polyclonal anti-RAB6KIFL antibody identified one of the cargoes transported by RAB6KIFL as discs, large homologue 5 (DLG5), a scaffolding protein that may link the vinexin-ß-catenin complex at sites of cell-cell contact. Like RAB6KIFL, DLG5 was overexpressed in PDACs, and knockdown of endogenous DLG5 by small interfering RNA significantly suppressed the growth of PDAC cells as well. Decreased levels of endogenous RAB6KIFL in PDAC cells altered the subcellular localization of DLG5 from cytoplasmic membranes to cytoplasm. Our results imply that collaboration of RAB6KIFL and DLG5 is likely to be involved in pancreatic carcinogenesis. These molecules should be promising targets for development of new therapeutic strategies for PDACs.

Key Words: pancreatic ductal adenocarcinoma • RAB6KIFL • kinesin • trafficking • DLG5

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