过氧化物酶体增殖物激活受体γ配体罗格列酮诱导人黑素瘤细胞系 A375 的生长抑制和分化。
Growth inhibition and differentiation induced by peroxisome proliferator activated receptor gamma ligand rosiglitazone in human melanoma cell line A375.
机构信息
Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100050 China.
出版信息
Med Oncol. 2006;23(3):393-402. doi: 10.1385/mo:23:3:393.
BACKGROUND
Ligands of peroxisome proliferator-activated receptors (PPARs) have been demonstrated to be antitumorgenic in vitro and in vivo due to their antiproliferative, prodifferential, and antiangiogenic effects. The aim of this study is to evaluate the effects and mechanisms of PPARgamma ligand rosiglitazone (ROZ) on the growth, apoptosis, and differentiation in human melanoma cancer cell line A375.
METHODS
The effects of ROZ on A375 cell proliferation were measured by clonogenic assay, apoptosis and cell cycle kinetics by FACS with ROZ for 72 h, PPARgamma protein was detected by Western blot analysis and immunocytochemical staining, and PPARgamma mRNA expression by RT-PCR. The differentiation effect of ROZ was determined by measurement of melanin content and tyrosinase activity. The levels of Bcl-2, P53, p-ERK, and ERK were also detected by Western blot analysis. Inhibition of tumorigensis was observed in nude mice.
RESULTS
ROZ inhibited colony formation and induced apoptosis in A375 cells, and the cells were arrested in G1 phase. This effect was associated with a decrease of the expression of Bcl-2 and increase of the expression of P53. ROZ also induced the differentiation in A375 cells. ROZ increased expression of PPARgamma and decreased the expression of ERK and p-ERK. Data in vivo showed that ROZ could inhibit tumorigensis in nude mice.
CONCLUSION
These results demonstrated that ROZ inhibited growth of A375 cells via the induction of apoptosis, necrosis, and differentiation in a PPARgamma-dependent manner and might present a promising therapeutic approach in certain human maligancies.
背景
过氧化物酶体增殖物激活受体（PPAR）的配体已被证明在体外和体内具有抗肿瘤作用，因为它们具有抗增殖、促分化和抗血管生成作用。本研究旨在评估 PPARγ 配体罗格列酮（ROZ）对人黑色素瘤 A375 细胞系生长、凋亡和分化的影响及其机制。
方法
用克隆形成实验测定 ROZ 对 A375 细胞增殖的影响，用 FACS 测定 ROZ 作用 72 h 后的细胞凋亡和细胞周期动力学，用 Western blot 分析和免疫细胞化学染色检测 PPARγ 蛋白，用 RT-PCR 检测 PPARγmRNA 表达。用黑色素含量和酪氨酸酶活性测定 ROZ 的分化作用。还通过 Western blot 分析检测 Bcl-2、P53、p-ERK 和 ERK 的水平。观察 ROZ 在裸鼠体内的抑瘤作用。
结果
ROZ 抑制 A375 细胞集落形成并诱导其凋亡，细胞停滞在 G1 期。这种作用与 Bcl-2 表达减少和 P53 表达增加有关。ROZ 还诱导 A375 细胞分化。ROZ 增加 PPARγ 的表达，降低 ERK 和 p-ERK 的表达。体内数据表明，ROZ 可抑制裸鼠肿瘤的发生。
结论
这些结果表明，ROZ 通过诱导凋亡、坏死和分化，以 PPARγ 依赖的方式抑制 A375 细胞的生长，可能为某些人类恶性肿瘤提供一种有前途的治疗方法。
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