Seriniquinone, a selective anticancer agent, induces cell death by autophagocytosis, targeting the cancer-protective protein dermcidin

TitleSeriniquinone, a selective anticancer agent, induces cell death by autophagocytosis, targeting the cancer-protective protein dermcidin
Publication TypeJournal Article
Year of Publication2014
AuthorsTrzoss L., Fukuda T, Costa-Lotufo L.V, Jimenez P., La Clair J.J, Fenical W
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Pagination14687-14692
Date Published2014/10
Type of ArticleArticle
ISBN Number0027-8424
Accession NumberWOS:000342922000030
Keywordsassays; autophagy; cancer; chemical biology; drug discovery; dye; elucidation; Marine natural; melanoma; mode of action; natural-products; products; update
Abstract

Natural products continue to provide vital treatment options for cancer. Although their translation into chemotherapeutics is complex, collaborative programs continue to deliver productive pipelines for cancer chemotherapy. A new natural product, seriniquinone, isolated from a marine bacterium of the genus Serinicoccus, demonstrated potent activity over a select set of tumor cell lines with particular selectivity toward melanoma cell lines. Upon entering the cell, its journey began by localization into the endoplasmic reticulum. Within 3 h, cells treated with seriniquinone underwent cell death marked by activation of autophagocytosis and gradually terminated through a caspase-9 apoptotic pathway. Using an immunoaffinity approach followed by multipoint validation, we identified the target of seriniquinone as the small protein, dermcidin. Combined, these findings revealed a small molecule motif in parallel with its therapeutic target, whose potential in cancer therapy may be significant. This discovery defines a new pharmacophore that displayed selective activity toward a distinct set of cell lines, predominantly melanoma, within the NCI 60 panel. This selectivity, along with the ease in medicinal chemical modification, provides a key opportunity to design and evaluate new treatments for those cancers that rely on dermcidin activity. Further, the use of dermcidin as a patient preselection biomarker may accelerate the development of more effective personalized treatments.

DOI10.1073/pnas.1410932111
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