Modulation of the sphingolipid rheostat is involved in paclitaxel resistance of the human prostate cancer cell line PC3-PR
Modulation of the sphingolipid rheostat is involved in paclitaxel resistance of the human prostate cancer cell line PC3-PR
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DOI：
10.1016/j.bbrc.2017.03.084
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发表时间：
2017-04-29
影响因子：
3.1
通讯作者：
Murate, Takashi
中科院分区：
文献类型：
--
作者：
Aoyama, Yuka;Sobue, Sayaka;Murate, Takashi
紫杉烷类是常用于治疗实体瘤的抗癌药物，但它们有时无效，肿瘤可能对其作用产生耐药性。在这里，我们研究了参与鞘脂代谢酶在紫杉醇（PTX）耐药使用人前列腺癌细胞系，PO，及其PTX耐药的亚系，PO-PR。PTX（20 nM）抑制细胞增殖，并增加各种神经酰胺的PO，但不PO-PR，细胞。无论FIX治疗如何，PO-PR的S1 P水平均高于PO。Western blotting结果显示，与PO细胞相比，PO-PR细胞表达较高水平的鞘氨醇激酶1（SPHK 1）和葡萄糖神经酰胺合酶（GCS），但表达较低水平的酸性鞘磷脂酶（ASMase）和中性鞘磷脂酶2。使用siRNA或药理学抑制剂抑制SPHK 1降低了PO-PR细胞中的SIP水平，并在存在或不存在PTX的情况下抑制增殖，这表明SPHK 1至少部分负责PTX抗性。GCS抑制剂（Psaline和PPMP）可增加细胞内神经酰胺的含量，抑制PO-PR的增殖，而抑制蛋白酶体功能或组蛋白脱乙酰酶活性则可增加SMase和神经酰胺的含量，抑制PO-PR的增殖。这些结果表明，代谢酶表达的调节和鞘脂变阻器的改变保护癌细胞免受PTX。(C)2017爱思唯尔公司All rights reserved.
Taxoids are anti-cancer drugs frequently used to treat solid tumors, but they are sometimes ineffective and tumors may become resistant to their action. Here, we examined the involvement of sphingolipid metabolic enzymes in paclitaxel (PTX) resistance using a human prostate cancer cell line, PO, and its PTX-resistant subline, PO-PR. PTX (20 nM) suppressed cell proliferation and increased various ceramide species in PO, but not PO-PR, cells. PO-PR contained higher S1P levels than did PO, regardless of FIX treatment. Western blotting revealed that PO-PR cells expressed higher levels of sphingosine kinase 1 (SPHK1) and glucosylceramide synthase (GCS) but lower levels of acid sphingomyelinase (ASMase) and neutral sphingomyelinase 2 than did PO cells. Inhibition of SPHK1 using siRNA or a pharmacological inhibitor decreased SIP levels in PO-PR cells and inhibited proliferation in the presence or absence of PTX, suggesting that SPHK1 is at least partially responsible for PTX resistance. Similarly, GCS inhibitors (PDMP and PPMP) increased cellular ceramides and suppressed the proliferation of PO-PR. However, inhibition of proteasome function or histone deacetylase activity increased SMase and ceramide levels and suppressed PO-PR proliferation. These results suggest that modulation of metabolic enzyme expression and alteration of the sphingolipid rheostat protects cancer cells against PTX. (C) 2017 Elsevier Inc. All rights reserved.