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

Sarwar, Martuza; Syed Khaja, Azharuddin Sajid; Aleskandarany, Mohammed; Karlsson, Richard; Althobiti, Maryam; �dum, Niels; Mongan, Nigel P.; Dizeyi, Nisthman; Johnson, Heather; Green, Andrew R.; Ellis, Ian O.; Rakha, Emad A.; Persson, Jenny L

Abstract

© 2018, The Author(s). 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 3 , and mean ISA-2011B-treated = 600 mm 3 , 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.

Citation

Sarwar, M., Syed Khaja, A. S., Aleskandarany, M., Karlsson, R., Althobiti, M., Ødum, N., …Persson, J. L. (2019). The role of PIP5K1α/pAKT and targeted inhibition of growth of subtypes of breast cancer using PIP5K1α inhibitor. Oncogene, 38(3), 375-389. https://doi.org/10.1038/s41388-018-0438-2

• Journal Article Type: Article
• Acceptance Date: Jul 16, 2018
• Online Publication Date: Aug 13, 2018
• Publication Date: Jan 17, 2019
• Deposit Date: Aug 14, 2018
• Publicly Available Date: Aug 14, 2018
• Journal: Oncogene
• Print ISSN: 0950-9232
• Electronic ISSN: 1476-5594
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 38
• Issue: 3
• Pages: 375-389
• DOI: https://doi.org/10.1038/s41388-018-0438-2
• Keywords: Genetics; Cancer Research; Molecular Biology
• Public URL: https://nottingham-repository.worktribe.com/output/1032020
• Contract Date: Aug 14, 2018