Role of SPTSSB-Regulated de Novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling.
Role of SPTSSB-Regulated de Novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling.
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DOI：
10.1016/j.isci.2020.101855
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发表时间：
2020-12-18
期刊：
影响因子：
5.8
通讯作者：
Kester M
中科院分区：
文献类型：
--
作者：
Costa-Pinheiro P;Heher A;Raymond MH;Jividen K;Shaw JJ;Paschal BM;Walker SJ;Fox TE;Kester M
抗雄激素是前列腺癌（PCa）中靶向雄激素受体（AR）信号传导的常用疗法。然而，这些疗法由于选择了没有可用治疗选择的高度侵袭性AR阴性癌细胞而失败。我们证明了通过施用外源性神经酰胺纳米脂质体（CNLs）来提高内源性神经酰胺水平在AR阴性细胞系中是有效的，而在AR阳性细胞中的功效有限。这种作用是通过减少AR阳性细胞中从头鞘脂合成介导的。我们发现，抗雄激素通过SPTSSB（鞘脂生成的限速介质）提高鞘脂的从头生成。此外，AR的药理学抑制通过从头合成增加了CNL在AR阳性细胞中的功效，而SPTSSB敲低限制了CNL在AR阴性细胞中的功效。提示临床相关性，SPTSSB在抗雄激素治疗后的晚期PCa患者中上调。这些发现强调了AR调节对鞘脂代谢的相关性以及CNL作为PCa治疗剂的潜力。AR阴性PCa细胞比AR阳性细胞对CNL更敏感抗雄激素和CNL的组合导致AR阳性PCa的功效增强AR通过SPTSSB负调节鞘脂的从头合成SPTSSB对于AR阴性PCa中的CNL效应至关重要并且在神经内分泌肿瘤中上调细胞生物学;癌症
Anti-androgens are a common therapy in prostate cancer (PCa) targeting androgen receptor (AR) signaling. However, these therapies fail due to selection of highly aggressive AR-negative cancer cells that have no therapeutic options available. We demonstrate that elevating endogenous ceramide levels with administration of exogenous ceramide nanoliposomes (CNLs) was efficacious in AR-negative cell lines with limited efficacy in AR-positive cells. This effect is mediated through reduced de novo sphingolipid synthesis in AR-positive cells. We show that anti-androgens elevate de novo generation of sphingolipids via SPTSSB, a rate-limiting mediator of sphingolipid generation. Moreover, pharmacological inhibition of AR increases the efficacy of CNL in AR-positive cells through de novo synthesis, while SPTSSB knockdown limited CNL's efficacy in AR-negative cells. Alluding to clinical relevance, SPTSSB is upregulated in patients with advanced PCa after anti-androgens treatment. These findings emphasize the relevance of AR regulation upon sphingolipid metabolism and the potential of CNL as a PCa therapeutic. AR-negative PCa cells are more susceptible to CNL than AR-positive cells Combination of anti-androgens and CNL results in enhanced efficacy for AR-positive PCa AR negatively regulates the de novo synthesis of sphingolipids through SPTSSB SPTSSB is crucial for CNL effect in AR-negative PCa and is upregulated in neuroendocrine tumors Cell Biology; Cancer
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影响因子：
8
作者：
McNair C;Urbanucci A;Comstock CE;Augello MA;Goodwin JF;Launchbury R;Zhao SG;Schiewer MJ;Ertel A;Karnes J;Davicioni E;Wang L;Wang Q;Mills IG;Feng FY;Li W;Carroll JS;Knudsen KE
通讯作者：
Knudsen KE
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
DOI：
10.1038/nrm.2017.107
发表时间：
2018-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Hannun YA;Obeid LM
通讯作者：
Obeid LM
DOI：
10.1073/pnas.0811269106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Han, Gongshe;Gupta, Sita D.;Dunn, Teresa M.
通讯作者：
Dunn, Teresa M.
影响因子：
5.2
作者：
Felici, A;Pino, M S;Carlini, Paolo
通讯作者：
Carlini, Paolo