Galectin-3 regulates mitochondrial stability and antiapoptotic function in response to anticancer drug in prostate cancer
Galectin-3 regulates mitochondrial stability and antiapoptotic function in response to anticancer drug in prostate cancer
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DOI：
10.1158/0008-5472.can-05-3750
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发表时间：
2006-03-15
期刊：
影响因子：
11.2
通讯作者：
Raz, A
中科院分区：
文献类型：
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作者：
Fukumori, T;Oka, N;Raz, A
前列腺癌是对抗癌药物表现出耐药性的恶性肿瘤之一，至少部分是由于增强的抗凋亡机制。因此，对此类机制的理解应该改善前列腺癌化疗的设计。 Galectin-3 (Gal-3) 是一种多功能致癌蛋白，参与肿瘤增殖、血管生成和细胞凋亡的调节，在某些细胞类型中显示出抗细胞凋亡作用。在这里，我们发现，在不组成型表达 Gal-3 的人前列腺癌 LNCaP 细胞中表达外源 Gal-3，可以通过稳定线粒体来抑制抗癌药物诱导的细胞凋亡。因此，用50μmol/L顺式二氨二氯铂处理48小时后，Gal-3阴性细胞出现66.31％的凋亡，而表达Gal-3的细胞的两个克隆仅显示2.92％和1.42％的凋亡细胞。同样，Gal-3阴性细胞用300 μmol/L依托泊苷处理48小时后，43.8%发生凋亡，而表达Gal-3的LNCaP细胞仅有15.38%和14.51%发生凋亡。 Gal-3 的表达刺激 Bcl-2 相关死亡 (Bad) 蛋白 Ser(112) 的磷酸化，并在顺式二氨二氯铂处理后下调 Bad 表达。 Gal-3 还抑制线粒体从细胞核转位至细胞质后的去极化和损伤，从而抑制细胞色素 c 的释放和 caspase-3 的激活。这些发现表明，Gal-3 通过调节 Bad 蛋白和抑制线粒体凋亡途径来抑制抗癌药物诱导的细胞凋亡。因此，靶向Gal-3可以提高前列腺癌抗癌药物化疗的疗效。
Prostate cancer is one of the malignant tumors which exhibit resistance to anticancer drugs, at least in part due to enhanced antiapoptotic mechanisms. Therefore, the understanding of such mechanisms should improve the design of chemotherapy against prostate cancer. Galectin-3 (Gal-3), a multifunctional oncogenic protein involved in the regulation of tumor proliferation, angiogenesis, and apoptosis has shown antiapoptotic effects in certain cell types. Here, we show that the expression of exogenous Gal-3 in human prostate cancer LNCaP cells, which do not express Gal-3 constitutively, inhibits anticancer drug-induced apoptosis by stabilizing the mitochondria. Thus, Gal-3-negative cells showed 66.31% apoptosis after treatment with 50 mu mol/L cis-diammine-dichloroplatinum for 48 hours, whereas two clones of Gal-3-expressing cells show only 2.92% and 1.42% apoptotic cells. Similarly, Gal-3-negative cells showed 43.8% apoptosis after treatment with 300 mu mol/L etoposide for 48 hours, whereas only 15.38% and 14.51% of Gal-3-expressing LNCaP cells were apoptotic. The expression of Gal-3 stimulated the phosphorylation of Ser(112) of Bcl-2-associated death (Bad) protein and down-regulated Bad expression after treatment with cis-diammine-dichloroplatinum. Gal-3 also inhibited mitochondrial depolarization and damage after translocation from the nuclei to the cytoplasm, resulting in inhibition of cytochrome c release and caspase-3 activation. These findings indicate that Gal-3 inhibits anticancer drug-induced apoptosis through regulation of Bad protein and suppression of the mitochondrial apoptosis pathway. Therefore, targeting Gal-3 could improve the efficacy of anticancer drug chemotherapy in prostate cancer.