Mycoplasma fermentans inhibits the activity of cellular DNA topoisomerase I by activation of PARP1 and alters the efficacy of its anti-cancer inhibitor.

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.

• Authors: Reuven Afriat, Shulamith Horowitz, Esther Priel
• Journal: PloS one (PLoS One) Vol. 8 Issue 8 Pg. e72377 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24013388 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Proteins
• Benzamides
• Poly(ADP-ribose) Polymerase Inhibitors
• Protein Kinase Inhibitors
• Proteins
• Topoisomerase I Inhibitors
• poly(ADP)-ribosylated proteins
• Poly Adenosine Diphosphate Ribose
• 3-aminobenzamide
• DNA
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• MAP Kinase Kinase Kinases
• DNA Topoisomerases, Type I
• TOP1 protein, human
• Camptothecin

Topics

• Bacterial Proteins (physiology)
• Benzamides (pharmacology)
• Camptothecin (pharmacology)
• DNA (metabolism)
• DNA Topoisomerases, Type I (metabolism)
• Drug Resistance, Neoplasm
• Enzyme Activation
• Host-Pathogen Interactions
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
• MAP Kinase Signaling System
• MCF-7 Cells
• Mycoplasma Infections (enzymology, microbiology)
• Mycoplasma fermentans (physiology)
• Poly (ADP-Ribose) Polymerase-1
• Poly Adenosine Diphosphate Ribose (metabolism)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proteins (metabolism)
• Topoisomerase I Inhibitors (pharmacology)