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
Department of Molecular Biology, Umeå University, Umeå, Sweden.
School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
Front Cell Dev Biol. 2022 Mar 21;10:798590. doi: 10.3389/fcell.2022.798590. eCollection 2022.
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.
磷脂酰肌醇-4-磷酸5-激酶1α（PIP5K1α）已成为治疗去势抵抗性前列腺癌（CRPC）的一个有前景的药物靶点，因为它在PI3K/AKT信号通路的上游发挥作用，促进前列腺癌（PCa）的生长、存活和侵袭。然而，在此过程中PIP5K1α的分子作用却鲜为人知。在此，我们表明，使用小分子抑制剂ISA-2011B通过siRNA介导敲低PIP5K1α以及阻断PIP5K1α的作用，可抑制CRPC细胞的生长和侵袭。我们证明，在CRPC细胞中靶向缺失PIP5K1α的N端结构域会导致癌细胞的生长和迁移能力降低。此外，与对照相比，缺乏PIP5K1α N端结构域的异种移植肿瘤在异种移植小鼠中表现出肿瘤生长减缓及侵袭性降低。PIP5K1α的N端结构域是调节PIP5K1α mRNA表达和蛋白质稳定性所必需的。这表明PIP5K1α的表达和致癌活性部分依赖于其N端结构域。我们进一步表明，PIP5K1α作为雄激素受体（AR）及其靶基因（包括CDK1和MMP9，它们是促进PCa细胞生长、存活和侵袭的关键因子）的上游调节因子发挥作用。ISA-2011B对具有野生型PIP5K1α的CRPC细胞以及缺乏PIP5K1α N端结构域的CRPC细胞中的AR靶基因（包括CDK1和MMP9）表现出显著的抑制作用。这些结果表明，PIP5K1α依赖性肿瘤的生长部分依赖于该激酶N端序列的完整性。我们的研究确定了一种涉及PIP5K1α的新功能机制，证实PIP5K1α是癌症治疗尤其是CRPC治疗的一个引人关注的靶点。
