Cross-talk between cancer and Pseudomonas aeruginosa mediates tumor suppression

Abstract

Microorganisms living at many sites in the human body compose a complex and dynamic community. Accumulating evidence suggests a significant role for microorganisms in cancer, and therapies that incorporate bacteria have been tried in various types of cancer. We previously demonstrated that cupredoxin azurin secreted by the opportunistic pathogen Pseudomonas aeruginosa, enters human cancer cells and induces apoptotic death1–4. However, the physiological interactions between P. aeruginosa and humans and their role in tumor homeostasis are largely unknown. Here, we show that P. aeruginosa upregulated azurin secretion in response to increasing numbers of and proximity to cancer cells. Conversely, cancer cells upregulated aldolase A secretion in response to increasing proximity to P. aeruginosa, which also correlated with enhanced P. aeruginosa adherence to cancer cells. Additionally, we show that cancer patients had detectable P. aeruginosa and azurin in their tumors and exhibited increased overall survival when they did, and that azurin administration reduced tumor growth in transgenic mice. Our results suggest host–bacterial symbiotic mutualism acting as a diverse adjunct to the host defense system via inter-kingdom communication mediated by the evolutionarily conserved proteins azurin and human aldolase A. This improved understanding of the symbiotic relationship of bacteria with humans indicates the potential contribution to tumor homeostasis.

Multi-omics differences in the bone marrow between essential thrombocythemia and prefibrotic primary myelofibrosis

“…Several studies investigating the relationship between Pseudomonas aeruginosa and cancer have shown that the blue cupredoxin azurin, secreted by this opportunistic pathogen, enters human cancer cells, leading to apoptosis [ 82 ]. Moreover, the presence of detectable Pseudomonas aeruginosa and azurin in the tumors of cancer patients has been linked to an increased overall survival rate [ 83 ]. Our results indicated that levels of Sphingomonas, Brevibacillus, and Pseudomonas_E were notably lower in pre-PMF than in ET, suggesting a potential contribution to the adverse features in patients with pre-PMF, pending further confirmation.…”

Peptide-Based Agents for Cancer Treatment: Current Applications and Future Directions

“…A peptide fragment, p28 (NSC745104) (CDG Therapeutics Inc., Elk Grove Village, IL, USA) ( Table 2 for peptides tested in clinical trials) derived from bacterial protein azurin also induces cell cycle arrest in various types of human cancer cells [ 16 , 17 ]. Cupredoxin azurin is secreted by the opportunistic pathogen Pseudomonas aeruginosa in response to increasing numbers of and proximity to cancer cells [ 18 , 19 , 20 , 21 , 22 ]. Secreted azurin preferentially enters a variety of solid tumor cell lines including breast cancers and induces p53-mediated apoptosis [ 18 , 19 , 23 , 24 , 25 ].…”

An Overview of Selected Bacterial Infections in Cancer, Their Virulence Factors, and Some Aspects of Infection Management

“…Since the initial observation of a bacterial anti-neoplastic role by German physician W. Busch in 1868 [143], the exploration of bacterial products/relevant mechanisms against cancer has been reported by many investigating groups throughout the world (Table 5) [144][145][146][147][148][149][150][151][152][153][154][155][156]. Different studies have identified a number of P. aeruginosa-released anticancer substances such as exotoxin A, mono-rhamnolipids, and azurin [157][158][159]. Overall, P. aeruginosa-linked anti-tumor mechanisms include the growth of bacteria in hypoxic regions of tumors, the production of toxins, modulation of host immune responses, and delivery of therapeutic genes that encode cytotoxic peptides or prodrug-converting enzymes [160] (Figure 2).…”