Loughran Ryan M, Arora Gurpreet K, Sun Jiachen, Llorente Alicia, Crabtree Sophia, Ly Kyanh, Huynh Ren-Li, Cho Wonhwa, Emerling Brooke M
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute; La Jolla, CA, USA.
Department of Chemistry, University of Illinois Chicago (UIC); Chicago, IL, USA.
bioRxiv. 2025 Jan 3:2025.01.02.629779. doi: 10.1101/2025.01.02.629779.
In p53-deficient cancers, targeting cholesterol metabolism has emerged as a promising therapeutic approach, given that p53 loss dysregulates sterol regulatory element-binding protein 2 (SREBP-2) pathways, thereby enhancing cholesterol biosynthesis. While cholesterol synthesis inhibitors such as statins have shown initial success, their efficacy is often compromised by the development of acquired resistance. Consequently, new strategies are being explored to disrupt cholesterol homeostasis more comprehensively by inhibiting its synthesis and intracellular transport. In this study, we investigate a previously underexplored function of PI5P4Ks, which catalyzes the conversion of PI(5)P to PI(4,5)P at intracellular membranes. Our findings reveal that PI5P4Ks play a key role in facilitating lysosomal cholesterol transport, regulating lysosome positioning, and sustaining growth signaling via the mTOR pathway. While PI5P4Ks have previously been implicated in mTOR signaling and tumor proliferation in p53-deficient contexts, this work elucidates an upstream mechanism that unifies these earlier observations.
在p53缺陷型癌症中，鉴于p53缺失会失调固醇调节元件结合蛋白2（SREBP - 2）通路，从而增强胆固醇生物合成，因此靶向胆固醇代谢已成为一种有前景的治疗方法。虽然他汀类等胆固醇合成抑制剂已显示出初步成效，但其疗效常因获得性耐药的出现而受到影响。因此，人们正在探索新的策略，通过抑制胆固醇合成和细胞内转运来更全面地破坏胆固醇稳态。在本研究中，我们研究了磷脂酰肌醇5 - 磷酸4 - 激酶（PI5P4Ks）此前未被充分探索的功能，该激酶可催化细胞内膜上磷脂酰肌醇5 - 磷酸（PI(5)P）向磷脂酰肌醇4,5 - 二磷酸（PI(4,5)P）的转化。我们的研究结果表明，PI5P4Ks在促进溶酶体胆固醇转运、调节溶酶体定位以及通过mTOR通路维持生长信号方面发挥着关键作用。虽然PI5P4Ks此前已被认为在p53缺陷情况下参与mTOR信号传导和肿瘤增殖，但这项工作阐明了一个统一这些早期观察结果的上游机制。
