Tianyan Wang
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.
Authors
Martuza Sarwar
Jonathan B. Whitchurch
HILARY COLLINS HILARY.COLLINS@NOTTINGHAM.AC.UK
Scientific Officer
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
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.
Citation
Wang, T., Sarwar, M., Whitchurch, J. B., Collins, H. M., Green, T., Semenas, J., …Persson, J. L. (2022). PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer. Frontiers in Cell and Developmental Biology, 10, Article 798590. https://doi.org/10.3389/fcell.2022.798590
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 |
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 |
Files
2022 FrontierCellDevBiol
(5.7 Mb)
PDF
Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
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