Novel role of ASC as a regulator of metastatic phenotype

Abstract

Disorders of cytoskeletal remodeling and signal transduction are frequently involved in cancer progression. In particular, apoptosis‐associated speck‐like protein containing a caspase‐recruitment domain (ASC) has been reported a proapoptotic molecule that is epigenetically silenced in several human cancers. ASC is a well‐characterized adaptor protein involved in the formation of multiprotein oligomers, called inflammasomes, and plays a crucial role in the activation and secretion of interleukin‐1β and interleukin‐18 in innate immune cells. However, the function of ASC in the regulation of tumor progression remains elusive. The present investigation examined the involvement of ASC in cancer progression and the acquisition of metastatic ability. To determine the effect of ASC depletion in in vitro and in vivo model systems, ASC was stably knocked down in B16 murine melanoma cell lines using retroviral transduction of shRNA. ASC suppression increased the motility of B16BL6 cells in scratch assays and augmented invasiveness as assessed by a Matrigel‐coated transwell system. Invadopodia formation and Src phosphorylation level were markedly enhanced in ASC‐knockdown cells as well. Since caspase‐8 has been reported to enhance cellular migration by Tyr380 phosphorylation via Src, we examined Tyr380 phosphorylation of caspase‐8 in ASC‐knockdown cells and found it to be elevated in ASC‐knockdown cells but attenuated by z‐VAD‐fmk or z‐IETD‐fmk. Moreover, ASC ablation increased pulmonary metastasis in mice after intravenous injection of B16BL6 cells. Our cumulative findings indicate that ASC suppresses cancer metastasis and progression via the modulation of cytoskeletal remodeling and the Src‐caspase‐8 signaling pathway.

Depletion of keratin 8/18 modulates oncogenic potential by governing multiple signaling pathways

“…In agreement with this, as shown in our differential proteomics data, there was a two‐ to sixfold upregulation of TMS1, a card domain containing apoptosis‐associated protein. TMS1 is shown to be epigenetically silenced in many cancers and is associated with their tumorigenic potential . These observations support our phenotypic analysis.…”

“…TMS1/ACS is known to be a potent regulator of TNF‐α‐mediated apoptosis and is epigenetically silenced during various malignancies . TMS1 was found to be upregulated in our quantitative proteomics data and further validated by western blot analysis (Fig.…”

The Inflammasome Adaptor ASC Intrinsically Limits CD4+ T-Cell Proliferation to Help Maintain Intestinal Homeostasis

“…The anti-proliferative nature of ASC (previously known as TMS-1) has also been linked to cancer progression (4). Indeed, it was found that the ASC promoter is highly methylated in several cancers, which silences ASC tumor-suppressor activity and permits cancer-cell propagation (31–36). Some other studies more broadly have implicated the NLRP3 inflammasome in cancer and links to proliferation of T cells/lymphoma cells.…”

Dual Role of Inflammasome Adaptor ASC in Cancer

“…An anti-tumor but not pro-apoptotic mechanism for ASC, which involves caspase-8, was identified in Okada et al (2016). The authors found that ASC ablation in murine tumor cell lines in vitro enhanced cellular motility and invadopodia formation through cytoskeletal reorganization, as well as Src accessibility to caspase-8 for ensuing phosphorylation (p-caspase-8 is prometastatic) and cellular migration.…”