p21 waf-1 (Cip-1) enhances apoptosis induced by manumycin and paclitaxel in anaplastic thyroid cancer cells
p21 waf-1 (Cip-1) enhances apoptosis induced by manumycin and paclitaxel in anaplastic thyroid cancer cells
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DOI：
10.1210/jc.2002-020992
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发表时间：
2003-02-01
影响因子：
5.8
通讯作者：
Yeung, SCJ
中科院分区：
文献类型：
--
作者：
Yang, HL;Pan, JX;Yeung, SCJ
我们之前的研究表明，手霉素（一种法尼基转移酶抑制剂）与紫杉醇联合使用可增强抗肿瘤活性并诱导细胞凋亡，以对抗未分化的甲状腺癌细胞。我们发现手霉素可诱导未分化甲状腺癌细胞中 p21 Waf-1 的内源性表达。 Manumycin 增加 p21 启动子的活性； p21 mRNA 的水平和 p21 蛋白的量。我们假设 p21 在用手霉素或紫杉醇或两种药物处理的细胞中具有促凋亡作用。通过测量活力和 caspase-3 活性，我们发现在金属硫蛋白启动子控制下用 p21 cDNA 稳定转染的 KAT-4 细胞在诱导 p21 时对单独的手霉素、单独的紫杉醇以及手霉素加紫杉醇更敏感。诱导 p21 的细胞敏感性增加与 caspase-3 活性增加（即细胞凋亡）相关。我们还发现，删除两个 p21 等位基因的细胞对手霉素加紫杉醇的敏感性低于其野生型亲代细胞。 p21本身的表达并不诱导细胞凋亡，但增强了手霉素和紫杉醇的细胞毒作用。这些发现表明，可能需要 p21 来维持细胞对手霉素和紫杉醇细胞毒性作用的敏感性。
Our previous studies demonstrated that manumycin (a farnesyltransferase inhibitor) enhanced the antineoplastic activity and induction of apoptosis when combined with paclitaxel against anaplastic thyroid cancer cells. We found that manumycin induces endogenous expression of p21 Waf-1 in anaplastic thyroid cancer cells. Manumycin increased the activity of the p21 promoter; the level of p21 mRNA, and the amount of p21 protein. We hypothesized that p21 had a proapoptotic effect in cells treated with manumycin, or paclitaxel, or both agents. By measuring viability and caspase-3 activity, we found that stably transfected KAT-4 cells with p21 cDNA under the control of a metallothionein promoter were more sensitive to manumycin alone, paclitaxel alone, and manumycin plus paclitaxel when p21 was induced. The increased sensitivity of the cells with induced p21 was associated with an increase in caspase-3 activity (i.e. apoptosis). We also found that cells with both p21 alleles deleted were less sensitive to manumycin plus paclitaxel than its wild-type parent cells. Expression of p21 per se did not induce apoptosis but enhanced the cytotoxic effects of manumycin and paclitaxel. These findings suggested that p21 might be required to maintain cell sensitivity to the cytotoxic effects of manumycin and paclitaxel.