Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 48, Pages 18356-18361Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0607240103
Keywords
calcium imaging; calcium release; display cloning; drug-induced side effects; hypersensitivity reactions
Categories
Funding
- NCCIH NIH HHS [R43 AT00324-01] Funding Source: Medline
- NIGMS NIH HHS [R01 GM063496, R01 GM059673, GM59673, GM63496] Funding Source: Medline
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Taxol (Paclitaxel) is an important natural product for the treatment of solid tumors. Despite a well documented tubulin-stabilizing effect, many side effects of taxol therapy cannot be explained by cytoskeletal mechanisms. In the present study submicromolar concentrations of taxol, mimicking concentrations found in patients, induced cytosolic calcium (Ca2+) oscillations in a human neuronal cell line. These oscillations were independent of extracellular and mitochondrial Ca2+ but dependent on intact signaling via the phosphoinositicle signaling pathway. We identified a taxol binding protein, neuronal Ca2+ sensor 1 (NICS-1), a Ca2+ binding protein that interacts with the inositol 1,4,5-trisphosphate receptor from a human brain cDNA phage display library. Taxol increased binding of NCS-1 to the inositol 1,4,5-trisphosphate receptor. Short hairpin RNA-mediated knockdown of NCS-1 in the same cell line abrogated the response to taxol but not to other agonists stimulating the phosphoinositide signaling pathway. These findings are important for studies involving taxol as a research tool in cell biology and may help to devise new strategies for the management of side effects induced by taxol therapy.
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