Sasakawa Yuka, Naoe Yoshinori, Sogo Naoki, Inoue Takeshi, Sasakawa Tatsuya, Matsuo Masahiko, Manda Toshitaka, Mutoh Seitaro
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
Biochem Pharmacol. 2005 Feb 15;69(4):603-16. doi: 10.1016/j.bcp.2004.11.008. Epub 2004 Dec 23.
In this study, we detected genes sensitive to an histone deacetylase inhibitor, FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo-[8,7,6]-tricos-16-ene-3,6,9,19,22-pentanone; FR901228, depsipeptide] in vitro and identified marker genes to predict sensitivity to FK228 in vivo using Affymetrix GeneChip. Three percent of genes (205/7070) were sensitive to FK228 in vitro, 105 and 100 genes, were up- and down-regulated, respectively, by FK228. Commonly up-regulated genes included p21(WAF1/Cip1), interleukin-8 (IL-8), histone family, JunB, caspase 9, mitogen-activated protein kinase phosphatase 1 (MKP-1) and mitogen-activated protein kinase (MAPK) family, and commonly down-regulated genes included cyclin A and MAPK family. One percent of genes (76/7070) showed native differences in patterns of expression, when FK228-sensitive (PC-3 prostate and SC-6-JCK (SC-6) stomach) and FK228-resistant (ACHN and A-498 renal) tumors implanted in BALB/c nu/nu mice were compared. Twenty-seven and forty nine of those genes were expressed at high or low levels, respectively, in FK228-sensitive tumors. Caspase 9 and MKP-1 genes showed distinct differences in patterns of expression between FK228-sensitive and resistant tumors and have been known to have roles in apoptosis and chromatin remodeling. The expression of caspase 9 gene was higher in FK228-sensitive tumors and the expression of MKP-1 gene was higher in FK228-resistant tumors. Caspase 9 and MKP-1 genes in the other FK228-sensitive tumors had the same patterns of expression as they did in PC-3 and SC-6 tumors. Our results present profiles of gene expression related to FK228 and marker genes to predict sensitivity to FK228, such as caspase 9 and MKP-1 genes.
在本研究中，我们在体外检测了对组蛋白脱乙酰酶抑制剂FK228[（E）-（1S，4S，10S，21R）-7-[(Z)-亚乙基]-4,21-二异丙基-2-氧杂-12,13-二硫杂-5,8,20,23-四氮杂双环-[8,7,6]-二十三碳-16-烯-3,6,9,19,22-戊酮；FR901228，缩肽]敏感的基因，并使用Affymetrix基因芯片鉴定了体内预测对FK228敏感性的标记基因。3%的基因（205/7070）在体外对FK228敏感，其中105个基因被FK228上调，100个基因被FK228下调。常见的上调基因包括p21（WAF1/Cip1）、白细胞介素-8（IL-8）、组蛋白家族、JunB、半胱天冬酶9、丝裂原活化蛋白激酶磷酸酶1（MKP-1）和丝裂原活化蛋白激酶（MAPK）家族，常见的下调基因包括细胞周期蛋白A和MAPK家族。当比较植入BALB/c裸鼠的FK228敏感肿瘤（PC-3前列腺癌和SC-6-JCK（SC-6）胃癌）和FK228耐药肿瘤（ACHN和A-498肾癌）时，1%的基因（76/7070）表现出表达模式的天然差异。其中27个和49个基因分别在FK228敏感肿瘤中高表达或低表达。半胱天冬酶9和MKP-1基因在FK228敏感和耐药肿瘤之间表现出明显的表达模式差异，并且已知它们在细胞凋亡和染色质重塑中发挥作用。半胱天冬酶9基因在FK228敏感肿瘤中的表达较高，而MKP-1基因在FK228耐药肿瘤中的表达较高。其他FK228敏感肿瘤中的半胱天冬酶9和MKP-1基因与它们在PC-3和SC-6肿瘤中的表达模式相同。我们的结果展示了与FK228相关的基因表达谱以及预测对FK228敏感性的标记基因，如半胱天冬酶9和MKP-1基因。
