Abstract
To understand the effects of the interaction between Mycoplasma and cells on the host cellular function, it is important to elucidate the influences of infection of cells with Mycoplasma on nuclear enzymes such as DNA Topoisomerase type I (Topo I). Human Topo I participates in DNA transaction processes and is the target of anti-cancer drugs, the camptothecins (CPTs). Here we investigated the mechanism by which infection of human tumor cells with Mycoplasma fermentans affects the activity and expression of cellular Topo I, and the anti-cancer efficacy of CPT. Human cancer cells were infected or treated with live or sonicated M. fermentans and the activity and expression of Topo I was determined. M. fermentans significantly reduced (by 80%) Topo I activity in the infected/treated tumor cells without affecting the level of Topo I protein. We demonstrate that this reduction in enzyme activity resulted from ADP-ribosylation of the Topo I protein by Poly-ADP-ribose polymerase (PARP-1). In addition, pERK was activated as a result of the induction of the MAPK signal transduction pathway by M. fermentans. Since PARP-1 was shown to be activated by pERK, we concluded that M. fermentans modified the cellular Topo I activity by activation of PARP-I via the induction of the MAPK signal transduction pathway. Moreover, the infection of tumor cells with M. fermentans diminished the inhibitory effect of CPT. The results of this study suggest that modification of Topo I activity by M. fermentans may alter cellular gene expression and the response of tumor cells to Topo I inhibitors, influencing the anti-cancer capacity of Topo I antagonists.
Highlights
Mycoplasmas, which belong to the Mollicutes class, are the smallest self-replicating eubacteria, devoid of a cell wall and surrounded only by a plasma membrane
Since Mycoplasma infect cells, including tumor cells, and this infection was previously shown to modify cell signaling [11,12,13,17], we examined the influence of M. fermentans strain K7 on an essential anti-cancer drug target, the cellular DNA Topoisomerase I, and the effect of this infection on its inhibitor Camptothecin (CPT), the derivatives of which are currently in clinical use as anti-cancer drugs
First we showed that the reduction in Topo I DNA relaxation activity was not a consequence of a decrease in the enzyme protein level; M. fermentans infection did not alter the expression of Topo I
Summary
Mycoplasmas, which belong to the Mollicutes class, are the smallest self-replicating eubacteria, devoid of a cell wall and surrounded only by a plasma membrane. Their small genome size (ranging from 580 to 1380 kbp) results in limited metabolic capabilities and parasitism [1,2]. Some Mycoplasma species are found as commensal inhabitants, while other were shown to be associated with infectious diseases and post-infection pathologies [3,4]. Most of the known Mycoplasma species are found as membrane surface parasites, and recently, some were shown to enter the cells and become intracellular residents [5]. Mycoplasma may cause chronic infections due to sophisticated mechanisms for evasion from immune surveillance (i.e., molecular mimicry, a unique type of antigenic variation), up-regulating or down-regulating cytokine secretion, adhesion molecules expression, transcription factors expression, MAP kinases activity, apoptotic pathways, and more [2,3]
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