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Decreased Expression and Function of -2 Macroglobulin Receptor/Low Density Lipoprotein Receptor-related Protein in Photodynamic Therapy-resistant Mouse Tumor Cells¹

Clayton Ocular Oncology Center [M. C. L., A. F., N. R., C. J. G.], Childrens Hospital Los Angeles, and Departments of Pediatrics, Radiation Oncology, and Molecular Pharmacology and Toxicology, University of Southern California [C. J. G.], Los Angeles, California 90027

Parental and photodynamic therapy (PDT)-resistant mouse, radiation-induced fibrosarcoma cell lines were evaluated using mRNA differential display in an attempt to identify unique transcripts. We detected one transcript that was consistently present in the parental cells but absent in PDT-resistant cells. The transcript was cloned, sequenced, and identified as -2 macroglobulin receptor/low density lipoprotein receptor-related protein (-2 MR/LRP). Northern and Western immunoblot analysis confirmed that receptor expression was present in the parental cell line but barely detectable in PDT-resistant cells. Functionality of the receptor was evaluated by exposing cells to Pseudomonas exotoxin A. -2 MR/LRP is responsible for Pseudomonas exotoxin A internalization, and only the parental cells exhibited toxin-mediated cytotoxicity. The binding and endocytosis of activated -2 macroglobulin and lipoproteins by -2 MR/LRP are consistent with modulating uptake and localization of photosensitizers. Our results demonstrate that PDT-resistant murine tumor cells exhibit minimal -2 MR/LRP activity and suggest that this receptor plays a role in PDT sensitivity by modulating photosensitizer uptake and/or subcellular localization.

¹ This work was performed in conjunction with the Clayton Foundation for Research and was supported in part by USPHS Grant R37-CA-31230 from the National Cancer Institute and Office of Naval Research Grant N00014-91-J-4047 from the Department of Defense.

² To whom requests for reprints should be addressed, at Clayton Ocular Oncology Center, Childrens Hospital Los Angeles, Mail Stop 67, 4650 Sunset Boulevard, Los Angeles, CA 90027.

Received 3/ 3/95. Accepted 3/21/95.

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