PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition.

Triscott, Joanna; Reist, Matthias; Küng, 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 (2023). PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition. Science Advances, 9(5), eade8641. American Association for the Advancement of Science 10.1126/sciadv.ade8641

[img]
Preview
Text
sciadv.ade8641.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (2MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

09 Interdisciplinary Units > Microscopy Imaging Center (MIC)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Triscott, Joanna Catherine Caprio, Reist, Matthias, Küng, Lukas, Lehner, Marika, De Brot, Simone Danielle, Rubin, Mark Andrew

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2375-2548

Publisher:

American Association for the Advancement of Science

Language:

English

Submitter:

Pubmed Import

Date Deposited:

02 Feb 2023 10:59

Last Modified:

20 Sep 2024 08:40

Publisher DOI:

10.1126/sciadv.ade8641

PubMed ID:

36724278

BORIS DOI:

10.48350/178285

URI:

https://boris.unibe.ch/id/eprint/178285

Actions (login required)

Edit item Edit item
Provide Feedback