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Apratoxin A shows novel pancreas-targeting activity through the binding of Sec 61

TitleApratoxin A shows novel pancreas-targeting activity through the binding of Sec 61
Publication TypeJournal Article
Year of Publication2016
AuthorsHuang K.C, Chen Z.H, Jiang Y.M, Akare S., Kolber-Simonds D., Condon K., Agoulnik S., TenDyke K, Shen Y.C, Wu K.M, Mathieu S., Choi H.W, Zhu X.J, Shimizu H., Kotake Y., Gerwick WH, Uenaka T., Woodall-Jappe M., Nomoto K.
JournalMolecular Cancer Therapeutics
Volume15
Pagination1208-1216
Date Published2016/06
Type of ArticleArticle
ISBN Number1535-7163
Accession NumberWOS:000377427600006
Keywordsanticancer agents; collection; cotranslational translocation; cyclodepsipeptide; endoplasmic-reticulum; inhibition; lyngbya-bouillonii; oxazoline analog; potent; protein; Translocation
Abstract

Apratoxin A is a natural product with potent antiproliferative activity against many human cancer cell lines. However, we and other investigators observed that it has a narrow therapeutic window in vivo. Previous mechanistic studies have suggested its involvement in the secretory pathway as well as the process of chaperone-mediated autophagy. Still the link between the biologic activities of apratoxin A and its in vivo toxicity has remained largely unknown. A better understanding of this relationship is critically important for any further development of apratoxin A as an anticancer drug. Here, we describe a detailed pathologic analysis that revealed a specific pancreas-targeting activity of apratoxin A, such that severe pancreatic atrophy was observed in apratoxin A-treated animals. Follow-up tissue distribution studies further uncovered a unique drug distribution profile for apratoxin A, showing high drug exposure in pancreas and salivary gland. It has been shown previously that apratoxin A inhibits the protein secretory pathway by preventing cotranslational translocation. However, the molecule targeted by apratoxin A in this pathway has not been well defined. By using a H-3-labeled apratoxin A probe and specific Sec 61 alpha/beta antibodies, we identified that the Sec 61 complex is the molecular target of apratoxin A. We conclude that apratoxin A in vivo toxicity is likely caused by pancreas atrophy due to high apratoxin A exposure. (C)2016 AACR.

DOI10.1158/1535-7163.mct-15-0648
Short TitleMol. Cancer Ther.
Student Publication: 
No
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