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

Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11103-8. doi: 10.1073/pnas.0701546104. Epub 2007 Jun 20.

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 (InsP(3))-mediated Ca(2+) signaling. We also observed a Taxol-specific reduction in neuronal calcium sensor 1 (NCS-1) protein levels, a known modulator of InsP(3) receptor (InsP(3)R) 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 Ca(2+) signaling. When NCS-1 protein levels recovered, so did InsP(3)-mediated Ca(2+) signaling. Inhibition of the Ca(2+)-activated protease mu-calpain prevented alterations in phosphoinositide-mediated Ca(2+) signaling and NCS-1 protein levels. We also found that NCS-1 is readily degraded by mu-calpain in vitro and that mu-calpain activity is increased in Taxol but not vehicle-treated cells. From these results, we conclude that prolonged exposure to Taxol activates mu-calpain, which leads to the degradation of NCS-1, which, in turn, attenuates InsP(3)mediated Ca(2+) signaling. These findings provide a previously undescribed approach to understanding and treating Taxol-induced peripheral neuropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling
  • Calpain / physiology
  • Cell Line
  • Cells, Cultured
  • Humans
  • Neuronal Calcium-Sensor Proteins / metabolism
  • Neurons / drug effects
  • Neuropeptides / metabolism
  • Paclitaxel / pharmacology*
  • Peripheral Nervous System Diseases / etiology
  • Phosphatidylinositols / metabolism*
  • Rats
  • Signal Transduction / drug effects*
  • Time Factors

Substances

  • Neuronal Calcium-Sensor Proteins
  • Neuropeptides
  • Phosphatidylinositols
  • frequenin calcium sensor proteins
  • Calpain
  • mu-calpain
  • Paclitaxel