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.
Highlights
Apoptosis-associated speck-like protein containing a caspase- recruitment domain (ASC) was originally identified as a component of the Triton X-100-insoluble fraction, called “speck”, of a retinoic acid-treated HL-60 cell line [1]
We previously reported that ASC expression was reduced in melanoma [7], colorectal cancer [8], lung cancer [9], and oral squamous cell carcinoma (OSCC) [10]
Since Liu et al [16] reported that ASC overexpression suppressed cell migration and invasion in renal cell carcinoma (RCC) cell lines, we examined the effects of ASC-knockdown on the cellular motility of B16BL6 cells in scratch assays
Summary
Apoptosis-associated speck-like protein containing a caspase- recruitment domain (ASC) was originally identified as a component of the Triton X-100-insoluble fraction, called “speck”, of a retinoic acid-treated HL-60 cell line [1]. In lung cancer, diminished expression of ASC was correlated with the invasive stages of tumor progression, and the ASC promoter was significantly hypermethylated in invasive lung adenocarcinoma patients with metastasis to the lymph nodes [9]. Other groups have identified relationships between silencing of the ASC gene by methylation and prognosis in prostate cancer [11, 12], glioblastoma [13], hepatocellular carcinoma [14], cervical cancer [15], and others. Liu et al [16] demonstrated that ASC was epigenetically inactivated in 41.1% of renal cell carcinoma (RCC) and suggested a role of tumor suppressor. Wu et al [17] reported that hypermethylation of the ASC/TMS1 promoter was significantly associated with greater lymph node metastasis, associated with a poor prognosis in patients with gastric cancer, and should be considered as a key prognostic indicator
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