High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation
High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation
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DOI：
10.1016/j.bbrc.2006.02.070
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发表时间：
2006-04-21
影响因子：
3.1
通讯作者：
Nozawa, Y
中科院分区：
文献类型：
--
作者：
Akao, Y;Banno, Y;Nozawa, Y
虽然大多数癌症的药物治疗利用细胞的凋亡机制，但由于前列腺癌细胞逃避抗癌药物诱导的凋亡的能力，可用的抗癌药物有限。人前列腺癌细胞系PC 3对喜树碱（CPT）具有抗性。为了阐明这种阻力的机制，我们已经研究了参与的鞘氨醇激酶（SPHK）和鞘氨醇1-磷酸（S1 P）受体在CPT耐药的PC 3和敏感的LNCaP细胞。与LNCaP细胞相比，PC 3细胞表现出更高的活性，同时SPHK 1的蛋白和mRNA表达水平更高，S1 P受体、S1 P和S1 P（3）的表达也更高。PC 3细胞中SPHK 1的小干扰RNA敲低和百日咳毒素对S1 P受体信号的抑制均能显著抑制细胞生长，提示SPHK 1和S1 P受体在PC 3细胞中的增殖中起重要作用。此外，发现用CPT处理PC 3细胞通过诱导SPHK 1酶和SIP 1/SIP 3受体来诱导SPHK 1/ SIP信号传导的上调。SPHK 1和S1 P受体的高表达和上调对CPT诱导的PC 3细胞凋亡具有保护作用。(c)2006年爱思唯尔公司All rights reserved.
Although most of pharmacological therapies for cancer utilize the apoptotic machinery of the cells, the available anti-cancer drugs are limited due to the ability of prostate cancer cells to escape from the anti-cancer drug-induced apoptosis. A human prostate cancer cell line PC3 is resistant to camptothecin (CPT). To elucidate the mechanism of this resistance, we have examined the involvement of sphingosine kinase (SPHK) and sphingosine 1-phosphate (S1P) receptor in CPT-resistant PC3 and -sensitive LNCaP cells. PC3 cells exhibited higher activity accompanied with higher expression levels of protein and mRNA of SPHK1 and also elevated expression of S1P receptors, S1P, and S1P(3), as compared with those of LNCaP cells. The knockdown of SPHK1 by small interfering RNA and inhibition of S1P receptor signaling by pertussis toxin in PC3 cells induced significant inhibition of cell growth, Suggesting implication of SPHK1 and S1P receptors in cell proliferation in PC3 cells. Furthermore, the treatment of PC3 cells with CPT was found to induce up-regulation of the SPHK1/ SIP signaling by induction of both SPHK1 enzyme and SIP1/SIP3 receptors. These findings strongly suggest that high expression and up-regulation of SPHK1 and S1P receptors protect PC3 cells from the apoptosis induced by CPT. (c) 2006 Elsevier Inc. All rights reserved.