A sigma-2 receptor agonist siramesine has been shown to trigger cell death of cancer cells and to exhibit a potent anticancer activity in vivo. However, its mechanism of action is still poorly understood. We show that siramesine can induce rapid cell death in a number of cell lines at concentrations above 20 μM. In HaCaT cells, cell death was accompanied by caspase activation, rapid loss of mitochondrial membrane potential (MMP), cytochrome c release, cardiolipin peroxidation and typical apoptotic morphology, whereas in U-87MG cells most apoptotic hallmarks were not notable, although MMP was rapidly lost. In contrast to the rapid loss of MMP above 20 μM siramesine, a rapid increase in lysosomal pH was observed at all concentrations tested (5-40 μM); however, it was not accompanied by lysosomal membrane permeabilisation (LMP) and the release of lysosomal enzymes into the cytosol. The lipophilic antioxidant α-tocopherol, but not the hydrophilic antioxidant N-acetyl-cysteine, considerably reduced cell death and destabilisation of mitochondrial membranes, but did not prevent the increase in lysosomal pH. At concentrations below 15 μM, siramesine triggered cell death after 2 days or later, which seems to be associated with a general metabolic and energy imbalance due to defects in the endocytic pathway, intracellular trafficking and energy production, and not by a specific molecular event. Overall, we show that cell death in siramesine-treated cells is induced by destabilisation of mitochondria and is independent of LMP and the release of cathepsins into the cytosol.
COBISS.SI-ID: 27111975
The endocytic pathway is a system specialized for the uptake of compounds from the cell microenvironment for their degradation. It contains an arsenal of hydrolases, including proteases, which are normally enclosed in membrane-bound organelles, but if released to the cytosol can initiate apoptosis signaling pathways. Endogenous and exogenous compounds have been identified that can mediate destabilization of lysosomal membranes, and it was shown that lysosomal proteases are not only able to initiate apoptotic signaling but can also amplify the apoptotic pathways initiated in other cellular compartments. The endocytic pathway also receives cargo destined for degradation via the autophagic pathway. By recycling energy and biosynthetic substrates, and by degrading damaged organelles and molecules, the endocytic system assists the autophagic system in resisting apoptotic stimuli. Steps leading to lysosomal membrane permeabilization and subsequent triggering of cell death as well as the therapeutic potential of intervention in lysosomal membrane permeabilization are discussed.
COBISS.SI-ID: 26621479