当前位置: X-MOL 学术iScience › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Role of SPTSSB-Regulated de Novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling
iScience ( IF 5.8 ) Pub Date : 2020-11-23 , DOI: 10.1016/j.isci.2020.101855
Pedro Costa-Pinheiro 1 , Abigail Heher 2 , Michael H Raymond 3 , Kasey Jividen 4 , Jeremy Jp Shaw 1 , Bryce M Paschal 4, 5 , Susan J Walker 6 , Todd E Fox 6 , Mark Kester 6, 7
Affiliation  

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.



中文翻译:

SPTSSB 调节的从头鞘脂合成在前列腺癌中的作用取决于雄激素受体信号传导

抗雄激素是针对雄激素受体 (AR) 信号传导的前列腺癌 (PCa) 的常见疗法。然而,由于选择了没有治疗选择的高侵袭性 AR 阴性癌细胞,这些疗法失败了。我们证明,通过施用外源性神经酰胺纳米脂质体 (CNL) 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 阳性细胞中的从头鞘脂合成来介导的。我们表明,抗雄激素通过SPTSSB提高了鞘脂的从头生成,鞘脂生成的限速介质。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。提到临床相关性,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。

更新日期:2020-12-04
down
wechat
bug