Mycoplasma Infection Enhances the Immunological Activation and the Warburg Effect of Metastatic Tumor Cells

Abstract

Mycoplasmas are the smallest, self‐replicating free‐living prokaryotes, and have been associated with carcinogenesis. Mycoplasmas can be detected in a large percentage and in a wide variety of primary human cancers. Some mycoplasma species such as M. fermentans and M. hyorhinis can transform normal murine and human cell lines into tumorigenic cells. Mycoplasma infection can activate oncogenes as well as inactivate tumor suppressor genes suggesting that mycoplasmas can be both carcinogenic and or onco‐modulatory. PCR amplification and sequencing showed that the metastatic murine VM‐M3 cell line (referred to as M3+) was infected with the mycoplasma M.arginini. Ciprofloxacin was used to eradicate M. arginini from M3+ cells (referred to as M3‐ cells). Metabolic markers of macrophage activation (itaconic acid, succinate, citrulline, and nitric oxide) were elevated in the M3+ cells when compared to the M3‐ cells. Respiration (oxygen consumption) was lower and fermentation (lactate production) was higher in the M3+ cells than in the M3‐ cells, indicating a larger Warburg effect in the M3+ cells. Both the M3+ and the M3‐ cells were positive for a Crabtree effect, as glucose suppressed the respiration of both the M3+ and the M3‐ cells. The in‐vitro proliferation rate of M3+ cells was faster than that of M3‐ cells. No significant difference was found, however, between the M3+ and M3‐ cells for subcutaneous tumor growth, as the immunocompetent VM/Dk inbred mouse host was able to eradicate the M. arginini infection from the M3+ cells when grown in vivo. The results suggest that M. arginini can enhance activation and the Warburg Effect of the murine VM‐M3 tumor cells.