The role of PIP5K1α/pAKT and targeted inhibition of growth of subtypes of breast cancer using PIP5K1α inhibitor

Abstract

Despite recent improvement in adjuvant therapies, triple-negative, and ER subtypes of breast cancer (BC) with metastatic potentials remain the leading cause of BC-related deaths. We investigated the role of phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), a key upstream factor of PI3K/AKT, and the therapeutic effect of PIP5Kα inhibitor on subtypes of BC. The clinical importance of PIP5K1α and its association with survivals were analyzed using three BC cohorts from Nottingham (n = 913), KM plotter (n = 112) and TCGA (n = 817). Targeted overexpression or knockdown of PIP5K1α were introduced into BC cell lines. The effects of PIP5K1α and its inhibitor on growth and invasion of BC were confirmed by using in vitro assays including proliferation, migration, apoptosis and luciferase reporter assays and in vivo xenograft mouse models. All statistical tests were two-sided. PIP5K1α was associated with poor patient outcome in triple-negative BC (for PIP5K1α protein, p = 0.011 and for mRNA expression, p = 0.028, log-rank test). 29% of triple-negative BC had PIP5K1A gene amplification. Elevated level of PIP5K1α increased expression of pSer-473 AKT (p < 0.001) and invasiveness of triple-negative MDA-MB-231 cells (p < 0.001). Conversely, inhibition of PIP5K1α using its inhibitor ISA-2011B, or via knockdown suppressed growth and invasiveness of MDA-MB-231 xenografts (mean vehicle-treated controls = 2160 mm, and mean ISA-2011B-treated = 600 mm, p < 0.001). ISA-2011B-treatment reduced expression of pSer-473 AKT (p < 0.001) and its downstream effectors including cyclin D1, VEGF and its receptors, VEGFR1 and VEGFR2 (p < 0.001) in xenograft tumors. In ER cancer cells, PIP5K1α acted on pSer-473 AKT, and was in complexes with VEGFR2, serving as co-factor of ER-alpha to regulate activities of target genes including cyclin D1 and CDK1. Our study suggests that our developed PIP5K1α inhibitor has a great potential on refining targeted therapeutics for treatment of triple-negative and ER BC with abnormal PI3K/AKT pathways.

PAK4 Kinase Activity Plays a Crucial Role in the Podosome Ring of Myeloid Cells

“…Importantly, subsequent removal of Akt inhibition restored podosome levels to control (Figure S3G). Recently, a phosphorylated Akt signal was detected at invadopodia (Sarwar et al., 2019); using the same antibody, we detected phosphorylated Akt within the podosome (Figure 3I). We do not detect a direct interaction between PAK4 and Akt; we would, therefore, suggest that an important role of PAK4 in podosome formation is the activation of the Akt pathway but not by direct phosphorylation of Akt.…”

The Great Escape: how phosphatidylinositol 4-kinases and PI4P promote vesicle exit from the Golgi (and drive cancer)

“…As an example, PIP5K1α is overexpressed in prostate cancer and is a poor prognostic indicator for this disease (283)(284)(285). Moreover, ISA-2011B -a small molecule inhibitor of PIP5K1α, is an effective anti-cancer agent in both prostate (285) and triple-negative breast cancer models (286). However, PIP5K1α has oncogenic functions outside of Golgi trafficking including the regulation of p53 oncoprotein stability in the nucleus (287) and KRAS signalling (288).…”

Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase

“…Our present study suggests that tumor-infiltrating cells are likely to be one of the major sources of the increased PIP5K1α and AKT activity observed in PCa. We have previously shown that the overexpression of PIP5K1α signaling resulted in aggressive tumor progression in several mouse models [ 16 , 18 , 26 ]. In this study, we found that PIP5K1α was highly expressed in PCa cells but was undetectable in bone marrow cells and the U-937 myeloid cell line.…”