Origin of anti-tumor activity of the cysteine-containing GO peptides and further optimization of their cytotoxic properties

Abstract

Antitumor GO peptides have been designed as dimerization inhibitors of prominent oncoprotein mucin 1. In this study we demonstrate that activity of GO peptides is independent of the level of cellular expression of mucin 1. Furthermore, these peptides prove to be broadly cytotoxic, causing cell death also in normal cells such as dermal fibroblasts and endometrial mesenchymal stem cells. To explore molecular mechanism of their cytotoxicity, we have designed and tested a number of new peptide sequences containing the key CxC or CxxC motifs. Of note, these sequences bear no similarity to mucin 1 except that they also contain a pair of proximal cysteines. Several of the new peptides turned out to be significantly more potent than their GO prototypes. The results suggest that cytotoxicity of these peptides stems from their (moderate) activity as disulfide oxidoreductases. It is expected that such peptides, which we have termed DO peptides, are involved in disulfide-dithiol exchange reaction, resulting in formation of adventitious disulfide bridges in cell proteins. In turn, this leads to a partial loss of protein function and rapid onset of apoptosis. We anticipate that coupling DO sequences with tumor-homing transduction domains can create a potentially valuable new class of tumoricidal peptides.

Interaction Between MUC1 and STAT1 Drives IFITM1 Overexpression in Aromatase Inhibitor–Resistant Breast Cancer Cells and Mediates Estrogen-Induced Apoptosis

“…Currently, a MUC1 third-generation inhibitor, GO-203, is undergoing phase I/II clinical trials for patients with acute myeloid leukemia (45,49). However, in vivo experiments within our laboratory have shown limited response to GO-201 and GO-201 demonstrates a cytotoxic effect on normal human fibroblasts (50). In addition to small-molecule inhibitors, MUC1 vaccines are also being investigated for their efficacy in multiple tumor types (51,52).…”

ACPred: A Computational Tool for the Prediction and Analysis of Anticancer Peptides

“…From these aforementioned studies, the researchers were able to determine key motifs responsible for the anticancer activity of GO-201 as CxC, thus reiterating the crucial role of Cys disulfide bridges [97]. Furthermore, Tyuryaeva et al [98] explored the molecular mechanism of Cys-induced cytotoxicity and the resulting apoptosis of cancer cells by designing and testing peptide sequences containing the key CxC ([R] 9 KCGCFF; named DIL) or CxxC ([R] 9 FF C PH C YQ; named DOL) motifs. The results obtained from this study suggests that the disulfide oxidoreductase is responsible for the effective cytotoxtic action of Cys.…”