Department for BioMedical Research, University of Bern, Bern 3008, Switzerland.
Institute of Biosciences, São Paulo State University, São Paulo, Brazil.
Sci Adv. 2023 Feb 3;9(5):eade8641. doi: 10.1126/sciadv.ade8641. Epub 2023 Feb 1.
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-P. 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.
磷脂酰肌醇（PI）调节酶在癌症中经常发生改变，已成为药物开发的重点。在这里，我们研究了磷脂酰肌醇-5-磷酸 4-激酶（PI5P4K），这是一类调节细胞内 PI 池的脂质激酶，并证实 PI5P4Kα 同工型影响雄激素受体（AR）信号，支持前列腺癌（PCa）细胞存活。我们表明，雄激素剥夺（AD）期间 PCa 的代谢应激适应会使 PI 的调节变得更加重要，因为 AD 会影响 PI 的丰度并增强 PI-4,5-P 的细胞内池。我们假设这种 PI5P4Kα-AR 关系通过 mTORC1 失调得到缓解，并表明 PI5P4Kα 与溶酶体共定位，溶酶体是 mTORC1 复合物激活的细胞内部位。值得注意的是，这种关系在手术后的小鼠前列腺组织中变得尤为明显。最后，多个 PCa 细胞模型在稳定抑制 PI5P4Kα 后表现出明显的存活脆弱性。这些结果将 PI5P4Kα 确定为破坏 PCa 代谢适应去势抵抗的靶标。
