Department of Molecular and Cell Biology, 91 North Eagleville Road, University of Connecticut, Storrs, CT 06269, United States.
Biochem Pharmacol. 2012 May 1;83(9):1217-28. doi: 10.1016/j.bcp.2012.01.024. Epub 2012 Jan 25.
Understanding how colon cancer cells survive within the inflammatory milieu of a tumor, and developing approaches that increase their sensitivity to inflammatory cytokines, may ultimately lead to novel approaches for colon cancer therapy and prevention. Analysis of a number of chemopreventive and therapeutic agents reveal that HDAC inhibitors are particularly adept at sensitizing colon cancer cells TNF or TRAIL mediated apoptosis. In vivo data are consistent with an interaction between SAHA and TNF in inducing apoptosis, as AOM-induced colon tumors express elevated levels of TNF and are more sensitive to SAHA administration. Cell cycle analysis and time-lapse imaging indicated a close correspondence between SAHA-induced prophase arrest and TNF or TRAIL-induced apoptosis. Prophase arrest induced by the Aurora kinase inhibitor VX680 likewise sensitized cells to TNF and TRAIL, with siRNA analysis pointing to Aurora kinase A (and not Aurora kinase B) as being the relevant target for this sensitization. We propose that agents that promote prophase arrest may help sensitize cancer cells to TNF and other inflammatory cytokines. We also discuss how circumvention of an early mitotic checkpoint may facilitate cancer cell survival in the inflammatory micro-environment of the tumor.
了解结肠癌细胞如何在肿瘤的炎症环境中存活，并开发出增加其对炎症细胞因子敏感性的方法，最终可能为结肠癌的治疗和预防提供新的方法。对许多化学预防和治疗药物的分析表明，HDAC 抑制剂特别擅长使结肠癌细胞对 TNF 或 TRAIL 介导的细胞凋亡敏感。体内数据与 SAHA 和 TNF 在诱导细胞凋亡中的相互作用一致，因为 AOM 诱导的结肠肿瘤表达高水平的 TNF，并且对 SAHA 给药更敏感。细胞周期分析和延时成像表明，SAHA 诱导的早前期阻滞与 TNF 或 TRAIL 诱导的细胞凋亡密切相关。Aurora 激酶抑制剂 VX680 诱导的早前期阻滞同样使细胞对 TNF 和 TRAIL 敏感，siRNA 分析表明 Aurora 激酶 A（而不是 Aurora 激酶 B）是这种敏感性的相关靶标。我们提出，促进早前期阻滞的药物可能有助于使癌细胞对 TNF 和其他炎症细胞因子敏感。我们还讨论了如何绕过早期有丝分裂检查点可能有助于癌细胞在肿瘤的炎症微环境中存活。
