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Raft-Dependent Endocytosis of Autocrine Motility Factor/Phosphoglucose Isomerase: A Potential Drug Delivery Route for Tumor Cells 1 2 1,2 1 3 3 Liliana D. Kojic , Sam M. Wiseman , Fariba Ghaidi , Bharat Joshi , Hinyu Nedev , H. Uri Saragovi , Ivan R. Nabi1* 1 Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada, 2 Department of Surgery, St. Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada, 3 Lady Davis Research Institute, McGill University, Montreal, Quebec, Canada Abstract Background: Autocrine motility factor/phosphoglucose isomerase (AMF/PGI) is the extracellular ligand for the gp78/ AMFR receptor overexpressed in a variety of human cancers. We showed previously that raft-dependent internalization of AMF/PGI is elevated in metastatic MDA-435 cells, but not metastatic, caveolin-1-expressing MDA-231 cells, relative to non-metastatic MCF7 and dysplastic MCF10A cells suggesting that it might represent a tumor cell-specific endocytic pathway. Methodology/Principal Findings: Similarly, using flow cytometry, we demonstrate that raft-dependent endocytosis of AMF/PGI is increased in metastatic HT29 cancer cells expressing low levels of caveolin-1 relative to metastatic, caveolin-1- expressing, HCT116 colon cells and non-metastatic Caco-2 cells. Therefore, we exploited the raft-dependent internalization of AMF/PGI as a potential tumor-cell specific targeting mechanism. We synthesized an AMF/PGI-paclitaxel conjugate and found it to be as efficient as free paclitaxel in inducing cytotoxicity and apoptosis in tumor cells that