The anticancer antibiotic mithramycin-A inhibits TRPV1 expression in dorsal root ganglion neurons

Abstract

Activation of peripheral nociceptors by products of inflammation has been shown to be dependent on specific sensory transducing elements such as the capsaicin receptor, TRPV1. The development of high-affinity antagonists to TRPV1 as well as to other receptors capable of detecting noxious stimuli has now become a major focus in analgesic development. Another critical feature of nociception is the relative abundance of a particular pain transducing receptor under normal or pathophysiologic conditions. Increases in expression and/or changes in distribution of nociceptive receptors such as TRPV1 have been correlated with progression of tissue injury and persistence of pain behaviors. Although some details are emerging as to what regulates nociceptor-specific gene expression, compounds that could potentially be used to block or reverse over-expression of nociceptive gene expression are essentially absent. In our efforts to better understand the transcriptional regulation of TRPV1 in sensory neurons, we identified an anticancer agent, mithramycin-A, that decreased TRPV1 expression in primary rat dorsal root ganglion (DRG) neurons. Mithramycin-A dose-dependently (10–50nM) decreased endogenous TRPV1 mRNA content and appeared to decrease TRPV1-like protein expression in DRG neurons. We also observed that mithramycin-A directed a decrease in the number of capsaicin-responsive DRG neurons without a significant change in the capsaicin-response magnitudes. Interestingly, mithramycin-A also reduced the mRNA encoding Sp1 and Sp4 in DRG neurons, transcription factors previously found to positively regulate TRPV1 expression in sensory neurons. Taken together, we propose that mithramycin-A directs an inhibitory effect on a subpopulation of capsaicin-responsive DRG neurons that utilize Sp1-like factors for TRPV1 expression. Given the therapeutic correlate of mithramycin-A effectiveness in the treatment of certain cancers, small molecule transcriptional inhibitors such as mithramycin-A may serve as useful tools of discovery in pain transduction and possibly future analgesic development.