Fujiwara Daichiro, Tsubaki Masanobu, Takeda Tomoya, Tomonari Yoshika, Koumoto Yu-Ichi, Sakaguchi Katsuhiko, Nishida Shozo
1 Division of Pharmacotherapy, School of Pharmacy, Kindai University, Higashi-Osaka, Japan.
2 Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan.
Tumour Biol. 2017 Oct;39(10):1010428317734947. doi: 10.1177/1010428317734947.
Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin by statins induced Bim expression via inhibition of Bim phosphorylation and ubiquitination and cell-cycle arrest at G1 phase via enhancement of p27 expression. Moreover, combined treatment of U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, and rapamycin, a mammalian target of rapamycin inhibitor, induced Bim and p27 expressions. The present results suggested that statins induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, enhancing Bim expression, and inducing cell-cycle arrest at G1 phase through inhibition of Ras/extracellular signal-regulated kinase and Ras/mammalian target of rapamycin pathways. Therefore, our findings support the use of statins as potential anticancer agents or concomitant drugs of adjuvant therapy.
最近，他汀类药物已被证明可改善各种癌症患者的癌症相关死亡率或预后。然而，其诱导凋亡的机制细节仍不清楚。本研究表明，他汀类药物在造血肿瘤细胞中诱导凋亡是由线粒体凋亡信号通路介导的，该通路通过抑制甲羟戊酸或香叶基香叶基焦磷酸生物合成而被激活。此外，他汀类药物通过抑制Ras异戊二烯化降低磷酸化细胞外信号调节激酶1/2和雷帕霉素靶蛋白的水平。此外，他汀类药物对细胞外信号调节激酶1/2和雷帕霉素靶蛋白的抑制通过抑制Bim磷酸化和泛素化诱导Bim表达，并通过增强p27表达诱导细胞周期停滞在G1期。此外，丝裂原活化蛋白激酶激酶1/2抑制剂U0126和雷帕霉素靶蛋白抑制剂雷帕霉素联合治疗可诱导Bim和p27表达。目前的结果表明，他汀类药物通过降低线粒体跨膜电位、增加caspase-9和caspase-3的激活、增强Bim表达以及通过抑制Ras/细胞外信号调节激酶和Ras/雷帕霉素靶蛋白途径诱导细胞周期停滞在G1期来诱导凋亡。因此，我们的研究结果支持将他汀类药物用作潜在的抗癌药物或辅助治疗的伴随药物。
