Piperlongumine induces inhibition of the ubiquitin-proteasome system in cancer cells

► Piperlongumine has been described to modulate redox and ROS homeostasis in cancer cells. ► We identified piperlongumine in a screen for agents that induce an unfolded protein response. ► Piperlongumine induces proteasome blocking and poly-ubiquitinated proteins in cells. ► Piperlongumine does not inhibit proteasome proteolytic activity or deubiquitinating activity. ► Induction of ROS by piperlongumine may be a consequence of inhibition of the UPS.