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Investigation of Staphylococcus aureus Biofilm-Associated Toxin as a Potential Squamous Cell Carcinoma Therapeutic
Zi Xin Ong1,2,3, Bavani Kannan1, Anthony R J Phillips4
1Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore.
Abstract:
Cancer therapies developed using bacteria and their components have been around since the 19th century. Compared to traditional cancer treatments, the use of bacteria-derived compounds as cancer therapeutics could offer a higher degree of specificity, with minimal off-target effects. Here, we explored the use of soluble bacteria-derived toxins as a potential squamous cell carcinoma (SCC) therapeutic. We optimized a protocol to generate Staphylococcus aureus biofilm-conditioned media (BCM), where soluble bacterial products enriched in the development of biofilms were isolated from a bacterial culture and applied to SCC cell lines. Bioactive components of S. aureus ATCC 29213 (SA29213) BCM display selective toxicity towards cancerous human skin SCC-12 at low doses, while non-cancerous human keratinocyte HaCaT and fibroblast BJ-5ta are minimally affected. SA29213 BCM treatment causes DNA damage to SCC-12 and initiates Caspase 3-dependent-regulated cell death. The use of the novel SA29213 bursa aurealis transposon mutant library led to the identification of S. aureus alpha hemolysin as the main bioactive compound responsible for the observed SCC-12-specific toxicity. The antibody neutralisation of Hla eradicates the cytotoxicity of SA29213 BCM towards SCC-12. Hla displays high SCC-12-specific toxicity, which is exerted primarily through Hla-ADAM10 interaction, Hla oligomerisation, and pore formation. The high target specificity and potential to cause cell death in a controlled manner highlight SA29213 Hla as a good candidate as an alternative SCC therapeutic.
Insights
Staphylococcus aureus biofilm-conditioned media shows selective toxicity against squamous cell carcinoma (SCC) cells. Alpha hemolysin (Hla) within the media is identified as the key component causing cancer cell death.
Area of Science:
- Microbiology
- Oncology
- Biochemistry
Background:
- Bacterial components have been explored as cancer therapies since the 19th century.
- Bacteria-derived compounds offer potential for targeted cancer treatment with fewer side effects.
- Squamous cell carcinoma (SCC) requires novel therapeutic strategies.
Purpose of the Study:
- To investigate soluble bacteria-derived toxins as a potential therapeutic for squamous cell carcinoma (SCC).
- To optimize the generation of Staphylococcus aureus biofilm-conditioned media (BCM) for therapeutic applications.
- To identify the specific bacterial components responsible for SCC cell toxicity.
Main Methods:
- Optimized protocol for generating Staphylococcus aureus biofilm-conditioned media (BCM).
- Treatment of SCC cell lines (SCC-12) and non-cancerous cells (HaCaT, BJ-5ta) with SA29213 BCM.
- Utilized a transposon mutant library to identify bioactive components and employed antibody neutralization for validation.
Main Results:
- SA29213 BCM demonstrated selective toxicity towards SCC-12 cells at low doses, sparing non-cancerous cells.
- BCM treatment induced DNA damage and Caspase 3-dependent cell death in SCC-12 cells.
- Staphylococcus aureus alpha hemolysin (Hla) was identified as the primary toxic component, mediating cell death via pore formation.
Conclusions:
- Staphylococcus aureus alpha hemolysin (Hla) is a potent and specific therapeutic candidate for squamous cell carcinoma.
- Hla's targeted toxicity mechanism, involving interaction with ADAM10 and pore formation, offers a promising alternative cancer treatment.
- Further development of Hla-based therapies could lead to more effective and less toxic SCC treatments.
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