Non-conventional rottlerin anticancer properties

Novel rottlerin targets (colored). Rottlerin arrests cell proliferation by binding and inhibiting ERK. Rottlerin inhibits mTORC1 both directly and by AMPK activation, causing autophagy and protein synthesis arrest through 4EBP1/eIF4E. Rottlerin causes ER stress and activation of eIF2α, which further represses mRNA translation. Established rottlerin targets (grey). ER stress can trigger the extrinsic apoptotic pathway through the CHOP/DR 5/caspase-8 cascade. Mitochondria uncoupling, by reducing ATP levels and increasing AMP, activates AMPK, which, in turn, inhibits mTORC1. At the same time, the collapse of the mitochondria inner membrane potential and the mitochondrial permeability transition pore (MPTP) opening trigger the intrinsic apoptotic pathway through the cytochrome C/apoptotic protease activating factor (Apaf) −1/caspase-9 cascade.181