Abstract
Prostate cancer is the most common malignancy, accounting for about 25% of all incident cases among men in industrialized countries. The human androgen-dependent prostate cancer cell line LNCaP, which is derived from a metastatic lesion of human prostatic adenocarcinoma, is frequently used to study prostate cancer associated signaling pathways in vitro. Recently it was described that Rho GTPase activation in these cells leads to apoptotic responses. We used the bacterial toxins CNFy and CNF1, which specifically and directly activate Rho GTPases by deamidation of a single glutamine. We asked whether these Rho activators could induce apoptosis in LNCaP cells. Our results indicate that RhoA activation, induced by CNFy, does lead to intrinsic apoptosis of the cells. Analysis of the underlying signaling pathway reveals that apoptosis induction requires the activity of Rho kinase (ROCK) and myosin activation, an apoptotic pathway previously identified in cancer stem cells.
Highlights
The bacterial toxins Cytotoxic Necrotizing Factor 1 (CNF1, secreted by pathogenic Escherichia coli strains) and Cytotoxic Necrotizing Factor Y (CNFy, produced by Yersinia pseudotuberculosis) activate Rho GTPases by deamidation of a single glutamine [1,2]
We asked whether direct activation of RhoA by the bacterial toxins CNF1 and CNFy is sufficient to induce an apoptotic response in mammalian cells
We asked which concentration of the toxin is sufficient to induce this effect. To this end we investigated the viability of the LNCaP cells following addition of a single dose of CNFy in a quantitative viability assay (WST-1) at 24 h and at 48 h of toxin treatment (Figure 4A)
Summary
The bacterial toxins Cytotoxic Necrotizing Factor 1 (CNF1, secreted by pathogenic Escherichia coli strains) and Cytotoxic Necrotizing Factor Y (CNFy, produced by Yersinia pseudotuberculosis) activate Rho GTPases by deamidation of a single glutamine [1,2]. Both toxins enter a wide spectrum of mammalian cells by receptor-mediated endocytosis [3]. We show that activation of RhoA by the specific Rho activator CNFy is sufficient to induce apoptosis in the prostate cancer cell line LNCaP. Further characterization of the underlying signaling pathway reveals that RhoA activation stimulates the intrinsic apoptotic pathway in LNCaP cells
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