Caveolin-1 promotes resistance to chemotherapy-induced apoptosis in Ewing's sarcoma cells by modulating PKCalpha phosphorylation.
Caveolin-1 promotes resistance to chemotherapy-induced apoptosis in Ewing's sarcoma cells by modulating PKCalpha phosphorylation.
复制标题
DOI：
10.1002/ijc.24754
复制
发表时间：
2010-01-15
影响因子：
6.4
通讯作者：
Notario, Vicente
中科院分区：
文献类型：
--
作者：
Tirado, Oscar M.;MacCarthy, Caitlin M.;Fatima, Naheed;Villar, Joaquin;Mateo-Lozano, Silvia;Notario, Vicente
Caveolin-1 (CAV1) 与多种信号通路的调节和肿瘤发生有关。此前，我们确定 CAV1 是尤文氏肉瘤家族 (ESFT) 肿瘤细胞的致癌表型和致瘤活性的关键决定因素。然而，迄今为止尚未确定 CAV1 可能参与 ESFT 亚群常见的化疗耐药。该报告表明，CAV1 表达决定 ESFT 细胞对临床相关化疗药物的敏感性。对几种 ESFT 细胞中内源性 CAV1 水平以及低内源性 CAV1 表达的 ESFT 细胞中异位 CAV1 表达的分析表明，CAV1 水平越高，其对药物治疗的抵抗力越大。此外，反义和shRNA介导的基因表达敲除和蛋白质重新表达实验的结果表明，CAV1通过涉及激活PKCα磷酸化的机制增加ESFT细胞对阿霉素（Dox）和顺铂（Cp）诱导的细胞凋亡的抵抗力。 ESFT 细胞中 CAV1 敲低导致磷酸 (Thr638)-PKCα 水平降低，并伴随对细胞凋亡敏感，而 CAV1 重新表达可逆转这一情况。这些结果通过 PKCα 敲低和在先前敲低 CAV1 的 ESFT 细胞中重新表达来概括，从而证明磷酸化 (Thr638)-PKCα 作用于 CAV1 下游，以确定 ESFT 细胞对化疗药物的敏感性。这些数据以及 CAV1 和磷酸化 (Thr638)-PKCα 在约 45% 的 ESFT 测试样本中共表达的发现表明，针对 CAV1 和/或 PKCα 可能允许开发新的分子治疗策略，以改善 ESFT 患者的治疗结果。
Caveolin-1 (CAV1) has been implicated in the regulation of several signaling pathways and in oncogenesis. Previously, we identified CAV1 as a key determinant of the oncogenic phenotype and tumorigenic activity of cells from tumors of the Ewing’s Sarcoma Family (ESFT). However, the possible CAV1 involvement in the chemotherapy resistance commonly presented by an ESFT subset has not been established to date. This report shows that CAV1 expression determines the sensitivity of ESFT cells to clinically relevant chemotherapeutic agents. Analyses of endogenous CAV1 levels in several ESFT cells and ectopic CAV1 expression into ESFT cells expressing low endogenous CAV1 showed that the higher the CAV1 levels, the greater their resistance to drug treatment. Moreover, results from antisense- and shRNA-mediated gene expression knockdown and protein re-expression experiments demonstrated that CAV1 increases the resistance of ESFT cells to doxorubicin (Dox)- and cisplatin (Cp)-induced apoptosis by a mechanism involving the activating phosphorylation of PKCα. CAV1 knockdown in ESFT cells led to decreased phospho(Thr638)-PKCα levels and a concomitant sensitization to apoptosis, which were reversed by CAV1 re-expression. These results were recapitulated by PKCα knockdown and re-expression in ESFT cells in which CAV1 was previously knocked down, thus demonstrating that phospho(Thr638)-PKCα acts downstream of CAV1 to determine the sensitivity of ESFT cells to chemotherapeutic drugs. These data, along with the finding that CAV1 and phospho(Thr638)-PKCα are co-expressed in ~45% of ESFT specimens tested, imply that targeting CAV1 and/or PKCα may allow the development of new molecular therapeutic strategies to improve the treatment outcome for ESFT patients.
登录
查看更多内容
影响因子：
45.3
作者：
Barker, LM;Pendergrass, TW;Hawkins, DS
通讯作者：
Hawkins, DS
DOI：
10.1046/j.1432-1327.2001.02326.x
发表时间：
2001-08-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Gill, PK;Gescher, A;Gant, TW
通讯作者：
Gant, TW
影响因子：
9.7
作者：
Aaltonen, Vesa;Koivunen, Jussi;Peltonen, Juha
通讯作者：
Peltonen, Juha
DOI：
10.1097/01.coc.0000135815.94162.83
发表时间：
2004-10-01
影响因子：
2.6
作者：
El Weshi, A;Memon, M;Ezzat, A
通讯作者：
Ezzat, A
影响因子：
12.7
作者：
Barresi, V.;Cerasoli, S.;Barresi, G.
通讯作者：
Barresi, G.