Protein kinase C-δ inactivation inhibits the proliferation and survival of cancer stem cells in culture and in vivo.
Protein kinase C-δ inactivation inhibits the proliferation and survival of cancer stem cells in culture and in vivo.
复制标题
DOI：
10.1186/1471-2407-14-90
复制
发表时间：
2014-02-14
期刊：
影响因子：
3.8
通讯作者：
Faller DV
中科院分区：
文献类型：
--
作者：
Chen Z;Forman LW;Williams RM;Faller DV
具有独特干细胞样特性的肿瘤细胞亚群（癌症干细胞样细胞，CSC）可能与肿瘤发生、侵袭性生长以及可能扩散到远处器官部位有关。 CSC 表现出一系列与干细胞表型一致的生物学、生化和分子特征，包括作为非粘附球体的生长（克隆潜力）、在异种移植测定中形成新肿瘤的能力、无限的自我更新以及多能性和谱系特异性分化的能力。 PKCδ 是 PKC 家族的一种新型丝氨酸/苏氨酸激酶，在许多细胞活动中发挥作用，包括细胞增殖、存活或凋亡。此前，使用遗传（shRNA 和显性失活 PKCδ 突变体）和小分子抑制剂，PKCδ 已被验证为多种类型的 Ras 信号传导异常激活的癌细胞中的合成致死靶点。相比之下，正常细胞的增殖或存活不需要 PKCδ，这表明 PKCδ 靶向方法具有潜在的肿瘤特异性。 shRNA 敲低用于验证 PKCδ 作为原发性癌症干细胞系和源自人类肿瘤细胞系（包括乳腺癌、胰腺癌、前列腺癌和黑色素瘤细胞）的干细胞样细胞的靶标。采用新型有效的小分子 PKCδ 抑制剂来监测这些癌症干细胞样群体的细胞凋亡、增殖和克隆形成能力。使用双尾学生 t 检验或方差分析确定数据集之间的显着差异。我们证明，源自多种类型的人类原发性肿瘤、人类癌细胞系和转化的人类细胞的 CSC 样群体需要 PKCδ 活性，并且对消耗 PKCδ 蛋白或活性的药物敏感。通过特定遗传策略 (shRNA) 或新型小分子抑制剂抑制 PKCδ 对培养中的多种类型的人类 CSC 具有生长抑制和细胞毒性。 PKCδ 抑制可有效防止肿瘤细胞培养物中肿瘤球的生长，暴露时间短至六小时。小分子 PKCδ 抑制剂还在小鼠异种移植模型中抑制体内人类 CSC 生长。这些发现表明，新型 PKC 同工酶 PKCδ 可能代表癌症干细胞群的新分子靶标。
A subpopulation of tumor cells with distinct stem-like properties (cancer stem-like cells, CSCs) may be responsible for tumor initiation, invasive growth, and possibly dissemination to distant organ sites. CSCs exhibit a spectrum of biological, biochemical, and molecular features that are consistent with a stem-like phenotype, including growth as non-adherent spheres (clonogenic potential), ability to form a new tumor in xenograft assays, unlimited self-renewal, and the capacity for multipotency and lineage-specific differentiation. PKCδ is a novel class serine/threonine kinase of the PKC family, and functions in a number of cellular activities including cell proliferation, survival or apoptosis. PKCδ has previously been validated as a synthetic lethal target in cancer cells of multiple types with aberrant activation of Ras signaling, using both genetic (shRNA and dominant-negative PKCδ mutants) and small molecule inhibitors. In contrast, PKCδ is not required for the proliferation or survival of normal cells, suggesting the potential tumor-specificity of a PKCδ-targeted approach. shRNA knockdown was used validate PKCδ as a target in primary cancer stem cell lines and stem-like cells derived from human tumor cell lines, including breast, pancreatic, prostate and melanoma tumor cells. Novel and potent small molecule PKCδ inhibitors were employed in assays monitoring apoptosis, proliferation and clonogenic capacity of these cancer stem-like populations. Significant differences among data sets were determined using two-tailed Student’s t tests or ANOVA. We demonstrate that CSC-like populations derived from multiple types of human primary tumors, from human cancer cell lines, and from transformed human cells, require PKCδ activity and are susceptible to agents which deplete PKCδ protein or activity. Inhibition of PKCδ by specific genetic strategies (shRNA) or by novel small molecule inhibitors is growth inhibitory and cytotoxic to multiple types of human CSCs in culture. PKCδ inhibition efficiently prevents tumor sphere outgrowth from tumor cell cultures, with exposure times as short as six hours. Small-molecule PKCδ inhibitors also inhibit human CSC growth in vivo in a mouse xenograft model. These findings suggest that the novel PKC isozyme PKCδ may represent a new molecular target for cancer stem cell populations.
登录
查看更多内容
影响因子：
12.4
作者：
Eramo, A.;Lotti, F.;De Maria, R.
通讯作者：
De Maria, R.
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Collins, AT;Berry, PA;Maitland, NJ
通讯作者：
Maitland, NJ
DOI：
10.1006/bbrc.1994.1199
发表时间：
1994-02-28
影响因子：
3.1
作者：
GSCHWENDT, M;MULLER, HJ;MARKS, F
通讯作者：
MARKS, F