Abstract
In order to further characterize its role in pathogenesis and to establish whether its overproduction can lead to eukaryotic tumor cell death, Salmonella strains able to express its virulence factor SpvB (an ADP-ribosyl transferase enzyme) in a salicylate-inducible way have been constructed and analyzed in different eukaryotic tumor cell lines. To do so, the bacterial strains bearing the expression system have been constructed in a ∆purD background, which allows control of bacterial proliferation inside the eukaryotic cell. In the absence of bacterial proliferation, salicylate-induced SpvB production resulted in activation of caspases 3 and 7 and apoptotic cell death. The results clearly indicated that controlled SpvB production leads to F-actin depolimerization and either G1/S or G2/M phase arrest in all cell lines tested, thus shedding light on the function of SpvB in Salmonella pathogenesis. In the first place, the combined control of protein production by salicylate regulated vectors and bacterial growth by adenine concentration offers the possibility to study the role of Salmonella effectors during eukaryotic cells infection. In the second place, the salicylate-controlled expression of SpvB by the bacterium provides a way to evaluate the potential of other homologous or heterologous proteins as antitumor agents, and, eventually to construct novel potential tools for cancer therapy, given that Salmonella preferentially proliferates in tumors.
Highlights
IntroductionTyphimurium) is probably the pathogen that has been most extensively studied and exploited as an anti-tumor agent
In this work we have used Salmonella for the ectopic expression of its virulence factor SpvB inside eukaryotic tumoral cell lines by using a salicylate inducible cascade expression system
Once Salmonella has infected a eukaryotic cell, bacterial proliferation leads to apoptosis induction and cell death within 18-24 hours due to the expression of certain effector proteins during the first 7-8 hours of infection
Summary
Typhimurium) is probably the pathogen that has been most extensively studied and exploited as an anti-tumor agent. It can invade different host cells, such as epithelial cells, macrophages and dendritic cells. Salmonella is capable of preferentially colonizing and proliferating in solid tumors to levels nearly 1000-fold higher than normal tissue, a situation that usually results in tumor growth inhibition [1]. The administration of attenuated Salmonella strains expressing different anti-tumor agents has been used in recent years with promising results in tumor regression [6,7,8,9]
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