PDF(Pubmed)
Abstract：
BACKGROUND: Pitavastatin is a cholesterol-lowering drug and is widely used clinically. In addition to this effect, pitavastatin has shown the potential to induce apoptosis in cutaneous squamous cell carcinoma (SCC) cells.
OBJECTIVE: The purpose of this study is to investigate the effects and possible action mechanisms of pitavastatin.
METHODS: SCC cells (SCC12 and SCC13 cells) were treated with pitavastatin, and induction of apoptosis was confirmed by Western blot. To examine whether pitavastatin-induced apoptosis is related to a decrease in the amount of intermediate mediators in the cholesterol synthesis pathway, the changes in pitavastatin-induced apoptosis after supplementation with mevalonate, squalene, geranylgeranyl pyrophosphate (GGPP) and dolichol were investigated.
RESULTS: Pitavastatin dose-dependently induced apoptosis of cutaneous SCC cells, but the viability of normal keratinocytes was not affected by pitavastatin at the same concentrations. In supplementation experiments, pitavastatin-induced apoptosis was inhibited by the addition of mevalonate or downstream metabolite GGPP. As a result of examining the effect on intracellular signaling, pitavastatin decreased Yes1 associated transcriptional regulator and Ras homolog family member A and increased Rac family small GTPase 1 and c-Jun N-terminal kinase (JNK) activity. All these effects of pitavastatin on signaling molecules were restored when supplemented with either mevalonate or GGPP. Furthermore, pitavastatin-induced apoptosis of cutaneous SCC cells was inhibited by a JNK inhibitor.
CONCLUSIONS: These results suggest that pitavastatin induces apoptosis of cutaneous SCC cells through GGPP-dependent JNK activation.
OBJECTIVE: The purpose of this study is to investigate the effects and possible action mechanisms of pitavastatin.
METHODS: SCC cells (SCC12 and SCC13 cells) were treated with pitavastatin, and induction of apoptosis was confirmed by Western blot. To examine whether pitavastatin-induced apoptosis is related to a decrease in the amount of intermediate mediators in the cholesterol synthesis pathway, the changes in pitavastatin-induced apoptosis after supplementation with mevalonate, squalene, geranylgeranyl pyrophosphate (GGPP) and dolichol were investigated.
RESULTS: Pitavastatin dose-dependently induced apoptosis of cutaneous SCC cells, but the viability of normal keratinocytes was not affected by pitavastatin at the same concentrations. In supplementation experiments, pitavastatin-induced apoptosis was inhibited by the addition of mevalonate or downstream metabolite GGPP. As a result of examining the effect on intracellular signaling, pitavastatin decreased Yes1 associated transcriptional regulator and Ras homolog family member A and increased Rac family small GTPase 1 and c-Jun N-terminal kinase (JNK) activity. All these effects of pitavastatin on signaling molecules were restored when supplemented with either mevalonate or GGPP. Furthermore, pitavastatin-induced apoptosis of cutaneous SCC cells was inhibited by a JNK inhibitor.
CONCLUSIONS: These results suggest that pitavastatin induces apoptosis of cutaneous SCC cells through GGPP-dependent JNK activation.
摘要：
背景：匹伐他汀是一种降胆固醇药物，临床上应用广泛。除了这个效果,匹伐他汀已显示出诱导皮肤鳞状细胞癌（SCC）细胞凋亡的潜力。
目的：本研究旨在探讨匹伐他汀的作用及可能的作用机制。
方法：用匹伐他汀处理SCC细胞（SCC12和SCC13细胞），通过Westernblot证实诱导细胞凋亡。为了检查匹伐他汀诱导的细胞凋亡是否与胆固醇合成途径中中间介质数量的减少有关，补充甲羟戊酸后，匹伐他汀诱导的细胞凋亡的变化，角鲨烯,研究了香叶基香叶基焦磷酸（G3GPP）和多立康醇。
结果：匹伐他汀剂量依赖性诱导皮肤SCC细胞凋亡，但相同浓度的匹伐他汀对正常角质形成细胞的活力没有影响。在补充实验中，添加甲羟戊酸或下游代谢物GGMP抑制了匹伐他汀诱导的细胞凋亡.作为检查对细胞内信号传导的影响的结果，匹伐他汀降低了Yes1相关的转录调节因子和Ras同源家族成员A，并增加了Rac家族小GTP酶1和c-JunN末端激酶（JNK）活性。匹伐他汀对信号分子的所有这些作用在补充有甲羟戊酸或GGb时恢复。此外，匹伐他汀诱导的皮肤SCC细胞凋亡被JNK抑制剂抑制。
结论：这些结果表明，匹伐他汀通过GPB依赖性JNK激活诱导皮肤SCC细胞凋亡。
目的：本研究旨在探讨匹伐他汀的作用及可能的作用机制。
方法：用匹伐他汀处理SCC细胞（SCC12和SCC13细胞），通过Westernblot证实诱导细胞凋亡。为了检查匹伐他汀诱导的细胞凋亡是否与胆固醇合成途径中中间介质数量的减少有关，补充甲羟戊酸后，匹伐他汀诱导的细胞凋亡的变化，角鲨烯,研究了香叶基香叶基焦磷酸（G3GPP）和多立康醇。
结果：匹伐他汀剂量依赖性诱导皮肤SCC细胞凋亡，但相同浓度的匹伐他汀对正常角质形成细胞的活力没有影响。在补充实验中，添加甲羟戊酸或下游代谢物GGMP抑制了匹伐他汀诱导的细胞凋亡.作为检查对细胞内信号传导的影响的结果，匹伐他汀降低了Yes1相关的转录调节因子和Ras同源家族成员A，并增加了Rac家族小GTP酶1和c-JunN末端激酶（JNK）活性。匹伐他汀对信号分子的所有这些作用在补充有甲羟戊酸或GGb时恢复。此外，匹伐他汀诱导的皮肤SCC细胞凋亡被JNK抑制剂抑制。
结论：这些结果表明，匹伐他汀通过GPB依赖性JNK激活诱导皮肤SCC细胞凋亡。
