From Beyond the Pale to the Pale Riders: The Emerging Association of Bacteria with Oral Cancer.

Oral cancer, predominantly oral squamous cell carcinoma (OSCC), is the eighth-most common cancer worldwide, with a 5-y survival rate <50%. There are numerous risk factors for oral cancer, among which periodontal disease is gaining increasing recognition. The creation of a sustained dysbiotic proinflammatory environment by periodontal bacteria may serve to functionally link periodontal disease and oral cancer. Moreover, traditional periodontal pathogens, such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola, are among the species most frequently identified as being enriched in OSCC, and they possess a number of oncogenic properties. These organisms share the ability to attach and invade oral epithelial cells, and from there each undergoes its own unique molecular dialogue with the host epithelium, which ultimately converges on acquired phenotypes associated with cancer, including inhibition of apoptosis, increased proliferation, and activation of epithelial-to-mesenchymal transition leading to increased migration of epithelial cells. Additionally, emerging properties of structured bacterial communities may increase oncogenic potential, and consortia of P. gingivalis and F. nucleatum are synergistically pathogenic within in vivo oral cancer models. Interestingly, however, some species of oral streptococci can antagonize the phenotypes induced by P. gingivalis, indicating functionally specialized roles for bacteria in oncogenic communities. Transcriptomic data support the concept that functional, rather than compositional, properties of oral bacterial communities have more relevance to cancer development. Collectively, the evidence is consistent with a modified polymicrobial synergy and dysbiosis model for bacterial involvement in OSCC, with driver mutations generating a conducive microenvironment on the epithelial boundary, which becomes further dysbiotic by the synergistic action of bacterial communities.

Sodium tungstate modulates ATM function upon DNA damage.

Both radiotherapy and most effective chemotherapeutic agents induce different types of DNA damage. Here we show that tungstate modulates cell response to DNA damaging agents. Cells treated with tungstate were more sensitive to etoposide, phleomycin and ionizing radiation (IR), all of which induce DNA double-strand breaks (DSBs). Tungstate also modulated the activation of the central DSB signalling kinase, ATM, in response to these agents. These effects required the functionality of the Mre11-Nbs1-Rad50 (MRN) complex and were mimicked by the inhibition of PP2A phosphatase. Therefore, tungstate may have adjuvant activity when combined with DNA-damaging agents in the treatment of several malignancies.

Anti-diabetic and anti-obesity agent sodium tungstate enhances GCN pathway activation through Glc7p inhibition.

Tungstate counteracts diabetes and obesity in animal models, but its molecular mechanisms remain elusive. Our Saccharomyces cerevisiae-based approach has found that tungstate alleviated the growth defect induced by nutrient stress and enhanced the activation of the GCN pathway. Tungstate relieved the sensitivity to starvation of a gcn2-507 yeast hypomorphic mutant, indicating that tungstate modulated the GCN pathway downstream of Gcn2p. Interestingly, tungstate inhibited Glc7p and PP1 phosphatase activity, both negative regulators of the GCN pathway in yeast and humans, respectively. Accordingly, overexpression of a dominant-negative Glc7p mutant in yeast mimicked tungstate effects. Therefore tungstate alleviates nutrient stress in yeast by in vivo inhibition of Glc7p. These data uncover a potential role for tungstate in the treatment of PP1 and GCN related diseases.

FK506 sensitizes mammalian cells to high osmolarity by modulating p38 MAP kinase activation.

The immunosuppressants tacrolimus (FK506) and cyclosporin A (CsA) have increased the survival rates in organ transplantation. Both drugs inhibit the protein phosphatase calcineurin (CaN) in activated T cells, exhibiting similar side-effects. Diabetes is observed more often in FK506 than CsA therapy, probably due to inhibition of new molecular targets other than CaN. We studied FK506 toxicity in mammalian cells. FK506, but not CsA, regulated p38 activation by osmotic stress, and decreased viability in osmostressed cells. In addition, FK506 treatment strongly increased the phosphorylation of the eukaryotic initiation factor-2alpha (eIF-2alpha) subunit. eIF-2alpha phosphorylation, p38 inhibition and cell lethality were relieved by addition of excess amino acids to the medium, suggesting that amino acid availability mediated FK506 toxicity. Therefore, these FK506-dependent responses could be relevant to the non-therapeutic effects of FK506 therapy.