A novel proteasome inhibitor acting in mitochondrial dysfunction, ER stress and ROS production

Abstract

Summary In cancer-treatment, potentially therapeutic drugs trigger their effects through apoptotic mechanisms. Generally, cell response is manifested by Bcl-2 family protein regulation, the impairment of mitochondrial functions, and ROS production. Notwithstanding, several drugs operate through proteasome inhibition, which, by inducing the accumulation and aggregation of misfolded or unfolded proteins, can lead to endoplasmic reticulum (ER) stress. Accordingly, it was shown that Amblyomin-X, a Kunitz-type inhibitor identified in the transcriptome of the Amblyomma cajennense tick by ESTs sequence analysis of a cDNA library, obtained in recombinant protein form, induces apoptosis in murine renal adenocarcinoma (RENCA) cells by: inducing imbalance between pro- and anti-apoptotic Bcl-2 family proteins, dysfunction/mitochondrial damage, production of reactive oxygen species (ROS), caspase cascade activation, and proteasome inhibition, all ER-stress inductive. Moreover, there was no manifest action on normal mouse-fibroblast cells (NHI3T3), suggesting an Amblyomin-X tumor-cell selectivity. Taken together, these evidences indicate that Amblyomin-X could be a promising candidate for cancer therapy.

Anticoagulants from Hematophagous

“…The prolongation of PT and aPTT is reversible [154]. Interestingly, several studies pointed out Amblyomin-X as an anti-cancer molecule in vitro and in vivo [154][155][156][157][158][159][160][161].…”

Arsenic trioxide induces programmed cell death through stimulation of ER stress and inhibition of the ubiquitin–proteasome system in human sarcoma cells

“…Furthermore, we found that the level of proteasome inhibition in HOS cells was higher than in HT1080 cells. Previous studies have demonstrated that proteasome inhibition induces cell death through ER stress [25,26]. Therefore, to detect the expression of the ER stress-related protein IRE1α, we performed western blotting with lysates from cells receiving each of the different concentrations of ATO (Fig.…”

“…The data accumulated thus far have revealed that ER stress leads to autophagy through the ER stress-induced inhibition of mTOR or direct activation of Atg pro-autophagic genes [26]. Therefore, we investigated whether inhibition of ER stress could change the percentage of apoptotic and autophagic cells that had been treated with ATO.…”

Metformin reduces the Walker-256 tumor development in obese-MSG rats via AMPK and FOXO3a

“…Bax and the adenine nucleotide translocator cooperate within the permeability transition pore complex, increasing mitochondrial membrane permeability. This increase in permeability results in the release of cytochrome c, apoptosis-inducing factor, and other pro-apoptotic molecules from the mitochondria into the cytoplasm, and consequently, these proteins can promote the activation of executioner caspases (3, 6 and 7), leading to apoptosis [15,43,47].…”