PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition.
PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition.
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DOI：
10.1126/sciadv.ade8641
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发表时间：
2023-02-03
期刊：
影响因子：
13.6
通讯作者：
Rubin, Mark A.
中科院分区：
文献类型：
--
作者：
Triscott, Joanna;Reist, Matthias;King, Lukas;Moselle, Francielle C.;Lehner, Marika;Gallon, John;Ravi, Archna;Arora, Gurpreet K.;de Brot, Simone;Lundquist, Mark;Gallart-Ayala, Hector;Ivanisevic, Julijana;Piscuoglio, Salvatore;Cantley, Lewis C.;Emerling, Brooke M.;Rubin, Mark A.
磷脂酰肌醇(PI)调节酶在癌症中经常发生改变，已成为药物开发的焦点。在这里，我们探索了磷脂酰肌醇-5-磷酸4-激酶(PI5P4K)，这是一种调节细胞内PI池的脂蛋白激酶家族，并证明了PI5P4Kα亚型影响雄激素受体(AR)信号转导，从而支持前列腺癌(Pca)细胞的生存。在雄激素剥夺(AD)过程中，PI的调节在PCA的代谢应激适应中变得越来越重要，因为我们发现AD影响了PI的丰度并增加了PI-4，5-P2的细胞内库。我们认为这种PI5P4Kα-AR关系可以通过mTORC1失调节来缓解，并表明PI5P4Kα共定位于溶酶体，溶酶体是mTORC1复合体激活的细胞内部位。值得注意的是，这种关系在手术去势后的小鼠前列腺组织中变得突出。最后，在稳定的PI5P4Kα抑制后，多个PCa细胞模型显示出显著的生存脆弱性。这些结果表明，PI5P4Kα是破坏Pca代谢适应去势抵抗的靶标。对PI5P4Kα代谢功能的了解显示了其在前列腺癌靶向治疗中的潜力。
Phosphatidylinositol (PI)regulating enzymes are frequently altered in cancer and have become a focus for drug development. Here, we explore the phosphatidylinositol-5-phosphate 4-kinases (PI5P4K), a family of lipid kinases that regulate pools of intracellular PI, and demonstrate that the PI5P4Kα isoform influences androgen receptor (AR) signaling, which supports prostate cancer (PCa) cell survival. The regulation of PI becomes increasingly important in the setting of metabolic stress adaptation of PCa during androgen deprivation (AD), as we show that AD influences PI abundance and enhances intracellular pools of PI-4,5-P2. We suggest that this PI5P4Kα-AR relationship is mitigated through mTORC1 dysregulation and show that PI5P4Kα colocalizes to the lysosome, the intracellular site of mTORC1 complex activation. Notably, this relationship becomes prominent in mouse prostate tissue following surgical castration. Finally, multiple PCa cell models demonstrate marked survival vulnerability following stable PI5P4Kα inhibition. These results nominate PI5P4Kα as a target to disrupt PCa metabolic adaptation to castrate resistance. An understanding of the metabolic function of PI5P4Kα shows potential for targeting it in prostate cancer.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
DOI：
10.1016/j.biocel.2013.03.009
发表时间：
2013-07-01
影响因子：
4
作者：
Elouarrat, Dalila;van der Velden, Yme U.;Haramis, Anna-Pavlina G.
通讯作者：
Haramis, Anna-Pavlina G.
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：
10.1042/bj20141333
发表时间：
2015-03-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Clarke JH;Giudici ML;Burke JE;Williams RL;Maloney DJ;Marugan J;Irvine RF
通讯作者：
Irvine RF
DOI：
10.1042/bj20090428
发表时间：
2009-07-29
期刊：
The Biochemical journal
影响因子：
--
作者：
Hammond GR;Schiavo G;Irvine RF
通讯作者：
Irvine RF