Molecular mechanism of Paclitaxel‐induced degradation of SCG10: a potential neuropathy biomarker (651.14)

Abstract

Peripheral neuropathy is a major disorder found in diabetic and chemotherapy‐treated cancer patients; it is commonly due to damage to nerve axons. Paclitaxel is a drug used as chemotherapy agent for the treatment of different types of cancer. The mode of action of Paclitaxel is affecting the microtubules’ dynamic instability required for the proper function of neuronal terminals and cell division. Paclitaxel promotes death of rapid dividing cells (i.e. cancer cells) and induces peripheral neuropathy as a side effect. However, the molecular mechanism that mediates Paclitaxel‐induced neuropathy is still unknown. We showed that the abundance of SCG10 ‐ a microtubule destabilizing protein ‐ decreased in Paclitaxel‐treated neuroblastoma cells. SCG10 protein levels are maintained in PC12 cells, when calpain is inhibited, indicating an involvement in the molecular mechanism activated by Paclitaxel‐treatment. In addition, the inhibition of JNKs after mechanical injured Dorsal Ganglion Root neurons blocks the reduction of SCG10 protein. Thus, JNKs may play an important role in Paclitaxel‐induced calpain‐mediated SCG10 protein degradation. Pharmacological and biochemical approaches were used to test this working hypothesis and identified other proteins associated with Paclitaxel‐induced SCG10 protein degradation. The results will contribute to the understanding of the molecular mechanism associated with the cellular respond to Paclitaxel treatment; information that could be used to prevent peripheral neuropathy as a side effect.Grant Funding Source: BP‐ENDURE NeuroID Program (8R25NS080687).