The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas
The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas
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DOI：
10.1038/sj.onc.1209065
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发表时间：
2006-01-01
期刊：
影响因子：
8
通讯作者：
Denning, MF
中科院分区：
文献类型：
--
作者：
D'Costa, AM;Robinson, JK;Denning, MF
蛋白激酶C(PKC)-Delta在角质形成细胞中是促凋亡的，在表达活化的Ha-ras癌基因的角质形成细胞中表达下调或失活，使其成为鳞状细胞癌的候选抑癌基因。我们使用显著降低PKC-Delta水平的致瘤HaCaT Ras II-4细胞来评估转化的人角质形成细胞中PKC-Delta丢失的意义。通过逆转录病毒转导重新表达PKC-Delta可增加细胞的凋亡率和生长抑制。PKC-Delta对细胞生长的抑制作用可被Bcl1-(Xl)部分逆转，提示细胞凋亡是PKC-Delta抑制细胞生长的部分原因。PKC-Delta的重新表达抑制了HaCaT Ras II-4细胞在裸鼠体内的致瘤性(P<；0.05)，而确实形成的小肿瘤含有激活的caspase-3水平升高，表明细胞凋亡增加。此外，我们发现29%(12/42)的人鲍温病(鳞状细胞原位癌)或鳞状细胞癌病例与周围正常表皮相比，PKC-Delta缺失或减少。这些结果表明，PKC-Delta通过诱导凋亡来抑制转化的角质形成细胞的生长，并且在人的SCCs中，PKC-Delta可能作为一种肿瘤抑制因子发挥作用，而其在含有活化的ras的细胞中的缺失可能通过提供对凋亡的抵抗而提供生长优势。
Protein kinase C (PKC)-delta is proapoptotic in human keratinocytes, and is downregulated or inactivated in keratinocytes expressing the activated Ha-ras oncogene, making it a candidate tumor suppressor gene for squamous cell carcinoma (SCC). We evaluated the significance of PKC-delta loss in transformed human keratinocytes using tumorigenic HaCaT Ras II-4 cells that have significantly reduced PKC-delta levels. Re-expression of PKC-delta by retro virus transduction caused an increase in apoptosis and growth inhibition in culture. The growth inhibition induced by PKC-delta could be partially reversed by Bcl-(xL) expression, indicating that apoptosis was in part responsible for PKC-delta-induced growth inhibition. PKC-delta re-expression suppressed the tumor-igenicity of HaCaT Ras II-4 cells in nude mice (P < 0.05), and the small tumors that did form contained elevated levels of activated caspase-3, indicating increased apoptosis. In addition, we found that 29% (12/42) of human Bowen's disease ( squamous carcinoma in situ) or SCC cases had absent or reduced PKC-delta when compared to the surrounding normal epidermis. These results indicate that PKC-delta inhibits transformed keratinocyte growth by inducing apoptosis, and that PKC-delta may function as a tumor suppressor in human SCCs where its loss in cells harboring activated ras could provide a growth advantage by conferring resistance to apoptosis.