Abstract
Introduction: Inadequate or inappropriate cell-substrate contact normally induces a form of apoptotic cell death termed anoikis. Malignant cells are often able to escape anoikis; this feature may contribute to their ability to form metastases. We hypothesized that carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) gene silencing would suppress anoikis resistance in pancreatic cancer cells. Methods: CEACAM6 was analyzed by Northern and Western blot. Anoikis was induced in PANC1, Capan2, MiaPaCa2 and MiaAR (an anoikis-resistant MiaPaCa2-derived sub-line) by polyHEMA culture and quantified by YO-PRO-1/propidium iodide flow cytometry (anoikis fraction). Caspase activity was quantified by fluorometric profiling and its contribution to anoikis confirmed with caspase inhibitor z-VAD-fmk. CEACAM6 expression was suppressed by siRNA (siCEACAM6). Metastatic ability was determined in an orthotopic nude mouse model. Results: CEACAM6 expression varied between cell lines, over-expression being associated with greater anoikis-resistance and in vivo metastatic ability. siCEACAM6 treatment suppressed native and acquired anoikis -resistance (see table) TABLE—ABSTRACT 7Cell lineAnoikis fraction in polyHEMA culture (Mean % ± SEM)UntreatedControl siRNAsiCEACAM6siCEACAM6 z-VAD-fmkcMiaPaCa214.1 ± 0.517 ± 0.523.4 ± 1.3∗3.0 ± 1.0‡MiaAR1.2 ± 0.5†2.5 ± 0.521.1 ± 1.1∗0.7 ± 0.5‡PANC115.1 ± 0.616.1 ± 0.933.6 ± 2.2∗7.3 ± 1.1‡Capan227.0 ± 1.1†29.2 ± 1.135.2 ± 2.4∗20.3 ± 1.8‡P < 0.01:∗vs control.†: vs MiaPaCa2.‡vs siCEACAM6. via increased caspase 3 and 8-acitvity (respective mean activities vs control in MiaPaCa2: 150% and 133%. MiaAR: 220% and 150%. P < 0.05), an effect abrogated by z-VAD-fmk. MiaAR metastasis was decreased from 100% of mice (median metastases: 3, range 0–8. n = 6) to 0% (n = 6. P < 0.05). Conclusion: CEACAM6 gene silencing promotes anoikis, reverses acquired anoikis resistance and inhibits metastasis in pancreatic adenocarcinoma. CEACAM6 warrants further investigation as a novel therapeutic target.
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