Steiner Federico A, Hong Julie A, Fischette Maria R, Beer David G, Guo Zong-Sheng, Chen G Aaron, Weiser Todd S, Kassis Edmund S, Nguyen Dao M, Lee Sunmin, Trepel Jane B, Schrump David S
Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA.
Oncogene. 2005 Mar 31;24(14):2386-97. doi: 10.1038/sj.onc.1208376.
cDNA arrays were used to examine gene induction in CALU-6 and H460 lung cancer cells mediated by sequential 5-aza 2'-deoxycytidine (DAC)/depsipeptide FK228 (DP) exposure in order to identify translational end points for clinical trials evaluating these agents. In both cell lines, sequential DAC/DP treatment induced expression of tissue factor pathway inhibitor-2 (TFPI-2), an inhibitor of Factor VII: tissue factor signal transduction known to diminish the malignant phenotype of cancer cells. TFPI-2 expression was diminished or absent in 16 of 32 cell lines established from thoracic malignancies. Sequential DAC/DP treatment induced TFPI-2 in cancer cells deficient for TFPI-2 expression in the basal state. Promoter methylation coincided with loss of TFPI-2 expression in a number of cancer lines. TFPI-2 promoter methylation was observed in one of five pulmonary adenocarcinomas, and seven of seven esophageal adenocarcinomas, but not corresponding normal tissues. DP enhanced acetylation of TFPI-2-associated histones in CALU-6 cells. DP or PDBU, alone, induced TFPI-2 expression in cancer cells deficient for TFPI-2 expression in the absence of promoter methylation. In these cells, DP-mediated TFPI-2 induction was abrogated by calphostin. Induction of TFPI-2 by distinct, yet cooperative mechanisms involving chromatin remodeling and PKC signaling strengthens the preclinical rationale for sequential administration of DNA demethylating agents and HDAC inhibitors in cancer patients. Furthermore, induction of TFPI-2 may be a useful surrogate marker of treatment response in individuals receiving sequential DAC/DP infusions.
使用cDNA阵列检测5-氮杂-2'-脱氧胞苷（DAC）/缩肽FK228（DP）序贯暴露介导的CALU-6和H460肺癌细胞中的基因诱导，以确定评估这些药物的临床试验的转化终点。在两种细胞系中，DAC/DP序贯治疗均诱导组织因子途径抑制剂-2（TFPI-2）的表达，TFPI-2是一种已知可减弱癌细胞恶性表型的VII因子：组织因子信号转导抑制剂。在从胸部恶性肿瘤建立的32个细胞系中的16个中，TFPI-2表达减弱或缺失。DAC/DP序贯治疗在基础状态下TFPI-2表达缺陷的癌细胞中诱导TFPI-2。启动子甲基化与许多癌症系中TFPI-2表达的丧失一致。在五例肺腺癌中的一例以及七例食管腺癌中的七例中观察到TFPI-2启动子甲基化，但相应的正常组织中未观察到。DP增强了CALU-6细胞中TFPI-2相关组蛋白的乙酰化。单独使用DP或PDBU可在不存在启动子甲基化的情况下，在TFPI-2表达缺陷的癌细胞中诱导TFPI-2表达。在这些细胞中，calphostin可消除DP介导的TFPI-2诱导。通过涉及染色质重塑和PKC信号传导的不同但协同的机制诱导TFPI-2，加强了癌症患者序贯给予DNA去甲基化剂和HDAC抑制剂的临床前理论依据。此外，TFPI-2的诱导可能是接受DAC/DP序贯输注的个体治疗反应的有用替代标志物。
