Acid ceramidase promotes nuclear export of PTEN through sphingosine 1-phosphate mediated Akt signaling.
Acid ceramidase promotes nuclear export of PTEN through sphingosine 1-phosphate mediated Akt signaling.
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DOI：
10.1371/journal.pone.0076593
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Beckham TH;Cheng JC;Lu P;Marrison ST;Norris JS;Liu X
肿瘤抑制因子PTEN现在被理解为调节细胞质膜上的细胞过程，在那里它经典地调节PI3K信号，以及在细胞核中，在控制细胞周期和基因组稳定性方面的多种作用已被阐明。已经描述了决定PTEN核输入和较少范围的核输出的机制，但是这些过程在疾病状态，特别是癌症中的相关性在很大程度上仍然未知。我们研究了酸性神经酰胺酶对PTEN核胞质转运的影响。人前列腺组织微阵列的免疫组化分析显示，在酸性神经酰胺酶升高的肿瘤患者中，核PTEN丢失。我们发现酸性神经酰胺酶促进核PTEN的减少，这依赖于鞘氨醇1-磷酸介导的Akt活化。我们进一步证明鞘氨醇1-磷酸促进了Crm1和PTEN之间复合物的形成，并且leptomycin B阻止酸性神经酰胺酶和鞘氨醇1-磷酸介导的核PTEN的丢失，这表明一个活跃的输出介导事件。为了研究酸性神经酰胺酶在前列腺癌中的促肿瘤作用是否取决于其从细胞核输出PTEN的能力，我们使用PTEN的强制核表达来研究多西他赛诱导的细胞凋亡、细胞杀伤、增殖和异种移植。有趣的是，虽然酸性神经酰胺酶能够保护表达野生型PTEN的细胞免受多西紫杉醇的侵袭，促进增殖和异种移植，但酸性神经酰胺酶对表达PTEN- nls的细胞没有影响。这些发现表明，酸性神经酰胺酶通过鞘氨醇1-磷酸促进PTEN的核输出，从而促进肿瘤形成、细胞增殖和对治疗的抵抗。
The tumor suppressor PTEN is now understood to regulate cellular processes at the cytoplasmic membrane, where it classically regulates PI3K signaling, as well as in the nucleus where multiple roles in controlling cell cycle and genome stability have been elucidated. Mechanisms that dictate nuclear import and, less extensively, nuclear export of PTEN have been described, however the relevance of these processes in disease states, particularly cancer, remain largely unknown. We investigated the impact of acid ceramidase on the nuclear-cytoplasmic trafficking of PTEN. Immunohistochemical analysis of a human prostate tissue microarray revealed that nuclear PTEN was lost in patients whose tumors had elevated acid ceramidase. We found that acid ceramidase promotes a reduction in nuclear PTEN that is dependent upon sphingosine 1-phosphate-mediated activation of Akt. We were further able to show that sphingosine 1-phosphate promotes formation of a complex between Crm1 and PTEN, and that leptomycin B prevents acid ceramidase and sphingosine 1-phosphate mediated loss of nuclear PTEN, suggesting an active exportin-mediated event. To investigate whether the tumor promoting aspects of acid ceramidase in prostate cancer depend upon its ability to export PTEN from the nucleus, we used enforced nuclear expression of PTEN to study docetaxel-induced apoptosis and cell killing, proliferation, and xenoengraftment. Interestingly, while acid ceramidase was able to protect cells expressing wild type PTEN from docetaxel, promote proliferation and xenoengraftment, acid ceramidase had no impact in cells expressing PTEN-NLS. These findings suggest that acid ceramidase, through sphingosine 1-phosphate, promotes nuclear export of PTEN as a means of promoting tumor formation, cell proliferation, and resistance to therapy.
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影响因子：
64.5
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