PubAg

Main content area

Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation

Author:
Boehmerle, Wolfgang, Zhang, Kun, Sivula, Michael, Heidrich, Felix M., Lee, Yashang, Jordt, Sven-Eric, Ehrlich, Barbara E.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.26 pp. 11103-11108
ISSN:
0027-8424
Subject:
calcium, calcium signaling, chronic exposure, drug therapy, ganglia, inositols, neoplasms, paclitaxel, peripheral nervous system diseases, proteinases, rats
Abstract:
Paclitaxel (Taxol) is a well established chemotherapeutic agent for the treatment of solid tumors, but it is limited in its usefulness by the frequent induction of peripheral neuropathy. We found that prolonged exposure of a neuroblastoma cell line and primary rat dorsal root ganglia with therapeutic concentrations of Taxol leads to a reduction in inositol trisphosphate (InsP₃)-mediated Ca²⁺ signaling. We also observed a Taxol-specific reduction in neuronal calcium sensor 1 (NCS-1) protein levels, a known modulator of InsP₃ receptor (InsP₃R) activity. This reduction was also found in peripheral neuronal tissue from Taxol treated animals. We further observed that short hairpin RNA-mediated NCS-1 knockdown had a similar effect on phosphoinositide-mediated Ca²⁺ signaling. When NCS-1 protein levels recovered, so did InsP₃-mediated Ca²⁺ signaling. Inhibition of the Ca²⁺-activated protease μ-calpain prevented alterations in phosphoinositide-mediated Ca²⁺ signaling and NCS-1 protein levels. We also found that NCS-1 is readily degraded by μ-calpain in vitro and that μ-calpain activity is increased in Taxol but not vehicle-treated cells. From these results, we conclude that prolonged exposure to Taxol activates μ-calpain, which leads to the degradation of NCS-1, which, in turn, attenuates InsP₃mediated Ca²⁺ signaling. These findings provide a previously undescribed approach to understanding and treating Taxol-induced peripheral neuropathy.
Agid:
2353103