Abstract 4408: Molecular mechanisms underlying cancer pain: Application of cellular models

Abstract

Abstract Pain is a major complaint in cancer patients. Little is known about the mechanisms leading to or maintaining cancer pain. This study is aimed to develop novel cellular models to study cancer pain. Isolated primary afferent sensory neurons were employed as a model system in order to produce cancer pain microenvironment in the presence of chemotherapeutic agents and cancer cells. Ca2+ imaging in sensory neurons showed increased [Ca2+]i within cancer pain microenvironment, suggesting a direct activation of sensory neurons. As a critical step in the initiation and transmission of pain cascades, release of pain neurotransmitters such as substance P and calcitonin-gene related peptide from primary afferent sensory neurons was studied and found to be significantly enhanced. As a result of sensory neuron activation, intracellular signaling transduction involving several major protein kinases was activated. For example, sub-apoptotic concentrations of paclitaxel (≤ 10 nM) potently elicit [Ca2+]i spikes, leading to PKA and PKC activation, and substance P release from primary afferent neurons. Moreover, AKAP150 was identified as a molecular mechanism synchronizing and transducing the activation of PKA to PKC. Our results reveal the presence of a specific cellular signaling pathway involving Ca2+/PKA/AKAP150/PKC(ε, βII, & Δ), independent of apoptosis, mediating pain neurotransmitter release and, ultimately, neuropathic pain induced by paclitaxel. Developing cellular models of cancer pain and identifying biomarkers/pathways may lead to novel diagnostic and therapeutic strategies for cancer pain. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4408. doi:10.1158/1538-7445.AM2011-4408