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Dual Role of Inflammasome Adaptor ASC in Cancer
Maria Pia Protti1,2, Lucia De Monte1,2
1Tumor Immunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
Abstract:
Apoptosis-associated Speck-like protein containing a CARD (caspase activation and recruitment domain) (ASC), also called PYCARD/Target of Methylation-induced Silencing-1 (TMS1), was originally discovered as a protein that forms aggregates ("specks") in human leukemia cells treated with chemotherapeutic agents. Its expression was found to be silenced by methylation in many human tumors, preventing tumor cells from undergoing apoptosis and supporting its role as a tumor suppressor. Subsequently, ASC was also identified as a central adaptor molecule of the inflammasome complex, which mediates the secretion of inflammatory cytokines (i.e., IL-1β and IL-18). Inflammatory cytokines have been shown to mediate tumor-promoting functions. Thus, in the context of cancer development and progression, ASC may exert opposing functions, i.e., be either tumor-suppressing by inducing tumor cell apoptosis, or tumor-promoting by favoring secretion of inflammatory cytokines (by tumor cells and/or tumor infiltrating myeloid cells) within the tumor microenvironment. Here, we report and discuss this dual role of ASC by also considering the final contribution of each of its two main functions in several cancer types, taking into consideration the correlation between ASC expression, clinical correlates, and patients' survival. ASC and inflammasome targeting strategies are being developed. However, before the use of such treatments in clinical practice, it is fundamental to better dissect the role of ASC in different tumors, in order to privilege or avoid their use in those tumors in which ASC exerts an anti-tumor or pro-tumor function, respectively.
Insights
Apoptosis-associated Speck-like protein (ASC) has a dual role in cancer, acting as a tumor suppressor by inducing apoptosis or a tumor promoter via inflammation. Understanding its function is crucial for developing targeted cancer therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Apoptosis-associated Speck-like protein containing a CARD (ASC) was initially identified as a tumor suppressor due to its role in apoptosis.
- ASC is also a key component of the inflammasome, mediating inflammatory cytokine secretion.
- Inflammatory cytokines can promote tumor development, suggesting a complex role for ASC in cancer.
Purpose of the Study:
- To investigate the dual role of ASC in cancer development and progression.
- To analyze the correlation between ASC expression, clinical outcomes, and patient survival across various cancer types.
- To discuss the implications of ASC's opposing functions for targeted cancer therapies.
Main Methods:
- Review and discussion of existing literature on ASC function in cancer.
- Analysis of correlations between ASC expression, clinical parameters, and patient survival.
- Consideration of ASC and inflammasome targeting strategies.
Main Results:
- ASC exhibits opposing functions in cancer: tumor suppression via apoptosis induction and tumor promotion via inflammation.
- The net effect of ASC on tumor progression depends on its specific functions within different cancer types and the tumor microenvironment.
- ASC expression levels correlate with clinical features and patient survival in certain cancers.
Conclusions:
- ASC plays a complex, context-dependent role in cancer, acting as both a tumor suppressor and promoter.
- Further research is needed to fully elucidate ASC's function in various tumors before clinical application of targeting strategies.
- Dissecting ASC's dual role is essential for optimizing the use of ASC and inflammasome-targeting cancer treatments.
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