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PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer

Wang, Tianyan; Sarwar, Martuza; Whitchurch, Jonathan B.; Collins, Hilary M.; Green, Tami; Semenas, Julius; Ali, Amjad; Roberts, Christopher J.; Morris, Ryan D.; Hubert, Madlen; Chen, Sa; El-Schich, Zahra; Wingren, Anette G.; Grundström, Thomas; Lundmark, Richard; Mongan, Nigel P.; Gunhaga, Lena; Heery, David M.; Persson, Jenny L.

PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer Thumbnail


Authors

Tianyan Wang

Martuza Sarwar

Jonathan B. Whitchurch

Tami Green

Julius Semenas

Amjad Ali

Christopher J. Roberts

Ryan D. Morris

Madlen Hubert

Sa Chen

Zahra El-Schich

Anette G. Wingren

Thomas Grundström

Richard Lundmark

NIGEL MONGAN nigel.mongan@nottingham.ac.uk
Professor of Oncology

Lena Gunhaga

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DAVID HEERY david.heery@nottingham.ac.uk
Professor of Eucaryotic Gene Regulation

Jenny L. Persson



Abstract

PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdown of PIP5K1α and blockade of PIP5K1α action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1α in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1α exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1α is required for regulation of mRNA expression and protein stability of PIP5K1α. This suggests that the expression and oncogenic activity of PIP5K1α are in part dependent on its N-terminal domain. We further show that PIP5K1α acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1α and in CRPC cells lacking the N-terminal domain of PIP5K1α. These results indicate that the growth of PIP5K1α-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1α, confirming that PIP5K1α is an intriguing target for cancer treatment, especially for treatment of CRPC.

Journal Article Type Article
Acceptance Date Feb 11, 2022
Online Publication Date Mar 21, 2022
Publication Date Mar 21, 2022
Deposit Date Apr 21, 2022
Publicly Available Date Apr 22, 2022
Journal Frontiers in Cell and Developmental Biology
Electronic ISSN 2296-634X
Publisher Frontiers Media SA
Peer Reviewed Peer Reviewed
Volume 10
Article Number 798590
DOI https://doi.org/10.3389/fcell.2022.798590
Keywords Cell Biology; Developmental Biology
Public URL https://nottingham-repository.worktribe.com/output/7784822
Publisher URL https://www.frontiersin.org/articles/10.3389/fcell.2022.798590/full