Abstract
Inflammatory caspases, including human caspase-4 (CASP4), play key roles in innate immune responses to promote fusion of phagosomes harboring pathogenic bacteria with lysosomes, halt intracellular replication of pathogens, maturation and secretion of pro-inflammatory cytokines. The role of inflammatory caspases in cancer cells remains poorly investigated. Here, we explored the consequences of modulating CASP4 expression levels on the migratory behavior of epithelial cancer cell lines. By a gene silencing approach and in vitro and in vivo studies we show that down-regulation of CASP4 leads to impaired cell migration and cell-matrix adhesion. This phenotype is accompanied by an increased actin cytoskeleton polymerization, changes in the overall organization of adherens junctions (AJs) and number and size of focal adhesions. Interestingly, the cell migration deficit could be reversed by epithelial growth factor treatment, and depletion of calcium ions unveiled a role of CASP4 in the novo assembly of AJs, suggesting that the role of CASP4 is not cell-autonomous. Finally, CASP4-silenced A431 cells exhibited a severe reduction in their ability to invade lung tissue, when injected into nude mice. Overall, our data support the emerging evidence that inflammatory caspases can regulate cell migration through actin remodeling and uncover a novel role of CASP4 in cancer cell behavior.
Highlights
During bacterial infection, different sensing systems cooperate to detect and control infections through the assembly of inflammasomes, high-molecular weight cellular complexes, with recruitment and activation of inflammatory caspases[1]
In order to investigate the effects of CASP4 modulation on cell growth, apoptosis and cell migration, cancer cell lines were transfected with small interfering RNA targeting CASP4
All small interfering RNA (siRNA) targeting exons coding for the pro-domain (#3) or the large p20 (#2) or the small p10 (#1) subunits strongly decrease CASP4 expression in A431 cells (Fig. 1a)
Summary
Different sensing systems cooperate to detect and control infections through the assembly of inflammasomes, high-molecular weight cellular complexes, with recruitment and activation of inflammatory caspases[1]. This in turn promotes the maturation and secretion of the pro-inflammatory interleukin (IL)-1β and IL-18 cytokines for controlling inflammatory responses and pyroptotic cell death[2,3]. Inflammatory caspases namely human and mouse caspase-1 (CASP1), human caspase-4 (CASP4) and caspase-5 (CASP5) and mouse caspase-11 (CASP11), are cysteine-aspartic proteases characterized by the presence of a caspase recruitment domain (CARD) at the N-terminus Both CASP11 and CASP4/5 bind intracellular lipopolysaccharide (LPS), the major structural element of Gram-negative bacteria outer membrane, with high specificity and affinity through their N-terminal CARD, leading to caspase activation and pyropoptotic death[4]. CASP4-silenced A431 cells exhibit a strikingly reduced invasive behavior upon dissemination to the lung of in vivo injected mice
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