Down-regulation of X-linked inhibitor of apoptosis synergistically enhanced peroxisome proliferator-activated receptor γ ligand-induced growth inhibition in colon cancer
Down-regulation of X-linked inhibitor of apoptosis synergistically enhanced peroxisome proliferator-activated receptor γ ligand-induced growth inhibition in colon cancer
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DOI：
10.1158/1535-7163.mct-08-0326
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发表时间：
2008-07-01
影响因子：
5.7
通讯作者：
Wong, Benjamin C. Y.
中科院分区：
文献类型：
--
作者：
Oiao, Liang;Dai, Yun;Wong, Benjamin C. Y.
我们之前发现，X-linked inhibitor of apoptosis protein （XIAP）是一种有效的内源性细胞凋亡抑制剂，在结肠癌中过表达。配体诱导的过氧化物酶体增殖体激活受体γ (PPAR γ)的激活已被证明在许多癌细胞类型中发挥促凋亡和抗增殖作用。然而，无论是单独下调XIAP还是使用PPAR γ配体的单药治疗都不足以控制结肠癌。我们探索XIAP抑制和pparty激活是否在结肠癌中提供协同抗癌作用。HCT116-XIAP（+/+）和HCT116-XIAP（-/-）细胞分别用曲格列酮或15-脱氧- δ(12,14)-前列腺素J(2) （15-PGJ(2)）处理。观察细胞生长和凋亡情况。裸鼠分别口服或不口服曲格列酮接种HCT116细胞。测量肿瘤生长、血管生成和细胞凋亡。曲格列酮-和15-PGJ(2)-诱导的生长抑制和凋亡在HCT116-XIAP（-/-）细胞中更为突出。Troglitazone-和15- pgj2诱导的细胞凋亡与caspases和poly(ADPribose) polymerase的切割增强相关，且在HCT116-XIAP（-/-）细胞中更为明显。用XIAP抑制剂1396-12预处理细胞也使HCT116-XIAP（+/+）细胞对PPAR γ配体诱导的凋亡敏感。曲格列酮显著延缓异种移植肿瘤的生长，对HCT116-XIAP（-/-）细胞源性肿瘤的抑制作用更为显著。肿瘤大小的减小与Ki-67、血管内皮生长因子和CD31的表达降低以及细胞凋亡增加有关。XIAP缺失显著使结直肠癌细胞对PPAR γ配体诱导的细胞凋亡和细胞增殖抑制敏感。因此，同时抑制XIAP和激活PPAR γ可能对结肠癌具有协同抗肿瘤作用。
We found previously that X-linked inhibitor of apoptosis protein (XIAP), a potent endogenous inhibitor of apoptosis, is overexpressed in colon cancer. Ligand-induced activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to exert proapoptotic and antiproliferative effects in many cancer cell types. However, neither XIAP down-regulation alone nor monotherapy using PPAR gamma ligands is potent enough to control colon cancer. We explored whether XIAP inhibition and PPARy activation offer a synergistic anticancer effect in colon cancer. HCT116-XIAP(+/+) and HCT116-XIAP(-/-) cells were treated with troglitazone or 15-deoxy-Delta(12,14)- prostaglandin J(2) (15-PGJ(2)). Cell growth and apoptosis were measured. Nude mice were s.c. inoculated with HCT116 cells with or without oral troglitazone. Tumor growth, angiogenesis, and apoptosis were measured. Troglitazone- and 15-PGJ(2)-induced growth inhibition and apoptosis were more prominent in HCT116-XIAP(-/-) cells. Troglitazone- and 15-PGJ2-induced apoptosis correlated with enhanced cleavage of caspases and poly(ADPribose) polymerase, which were more profound in HCT116-XIAP(-/-) cells. Pretreatment of cells with XIAP inhibitor 1396-12 also sensitized HCT116-XIAP(+/+) cells to PPAR gamma ligand-induced apoptosis. Troglitazone significantly retarded the growth of xenograft tumors, more significantly so in HCT116-XIAP(-/-) cell-derived tumors. Reduction of tumor size was associated with reduced expression of Ki-67, vascular endothelial growth factor, and CD31 as well as increased apoptosis. Loss of XIAP significantly sensitized colorectal cancer cells to PPAR gamma ligand-induced apoptosis and inhibition of cell proliferation. Thus, simultaneous inhibition of XIAP and activation of PPAR gamma may have a synergistic antitumor effect against colon cancer.