The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer

Semenas, Julius; Hedblom, Andreas; Miftakhova, Regina; Sarwar, Martuza; Larsson, Rikard; Shcherbina, Liliya; Johansson, Martin; Härkönen, Pirkko; Sterner, Olov; Persson, Jenny L.

doi:10.1073/pnas.1405801111

Cited by 95 publications

(140 citation statements)

References 41 publications

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“…PIP2 is phosphorylated by PI3K to generate PI-3,4,5-P 3 (PIP3), which recruits the serine/threonine kinase AKT to the cell membrane, where it becomes activated, initiating signaling cascades. In this study, Semenas et al (3) find that PIP5K1α is overexpressed in high-grade prostate cancer, and its expression correlates with PIP2 and AR expression in these tissues. The authors further demonstrate that PIP5K1α contributed to malignant transformation in prostate cancer cell lines through increased invasion, enhanced stability or expression of AR, and expression of cellular proliferation markers such as cyclin-dependent kinase 1 (CDK1).…”

supporting

confidence: 50%

PIP5K1α inhibition as a therapeutic strategy for prostate cancer

Drake

Huang

2014

Proc. Natl. Acad. Sci. U.S.A.

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supporting

confidence: 50%

PIP5K1α inhibition as a therapeutic strategy for prostate cancer

Drake

Huang

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Our results demonstrated that EPA decreased cancer proliferation more efficiently compared with DHA, suggesting a possible treatment for metastatic castration-resistant prostate cancer. In addition, PC3 cells expressed phosphoinositide 3 kinase (PI3K)/AKT-related PIP5K1α (15), and HBx transfection in HepG2 cells led to the expression of nuclear factor (NF)-κβ (16). NF-κβ is downstream of PI3K/AKT and is a transcription factor that acts on a variety of genes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PC3 human prostate cancer cell proliferation, invasion and migration by eicosapentaenoic acid and docosahexaenoic acid

et al. 2017

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Abstract. The n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found in fish oil, exert a number of beneficial effects, and they are used in the treatment of hyperlipidemia. In recent years, EPA and DHA have been found to affect cancer cell proliferation. In the present study, PC3 cells, which are androgen-independent prostate cancer cells that resemble castration-resistant prostate cancer cells, were used to investigate a possible novel treatment for castration-resistant prostate cancer. The PC3 cells were cultured and incubated with various concentrations of EPA or DHA. Cancer proliferation was confirmed by trypan blue microscopy. Invasion and migration assays were used in the upper chamber in PC3 cells, and serum-free medium and various concentrations of EPA or DHA were placed in the lower chamber in serum-containing medium. EPA and DHA decreased PC3 cell proliferation, invasion and migration. The effect of EPA on PC3 cells was dose-dependent and significant differences were observed at concentrations of 100 and 200 µg/ml. The effect of DHA on PC3 cells was similar to that of EPA. In the migration assay, EPA exerted almost no effects at 25 µg/ml, but migration was reduced at 50 µg/ml. Similar to EPA, DHA exerted almost no effects at 25 µg/ml, but further reduction was observed at the 50 µg/ml concentration. In the invasion assay, EPA at 25 µg/ml was not significantly different from the control, but suppressed invasion at 50 µg/ml. DHA decreased invasion compared with the control at 25 µg/ml, whereas invasion was significantly reduced at a DHA concentration of 50 µg/ml. In conclusion, it was demonstrated that EPA and DHA were effective in decreasing the proliferation, invasion and migration of prostate PC3 cancer cells. However, the detailed underlying mechanisms have not yet been fully elucidated. IntroductionEicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids that have several beneficial effects, including decreasing the plasma triglyceride concentration, lipoprotein metabolism (1,2), inhibiting platelet aggregation by collagen (3), and improving the reduced elasticity of the arterial walls through the endothelium-dependent relaxation response in rabbits (4). For these reasons, DHA and EPA are clinically used in Japan. In recent years, n-3 fatty acids have been shown to decrease the proliferation of cancer cells in colon, breast and liver cancer, as well as neuroblastoma. In addition, n-3 fatty acids may be used in cancer cachexia; the combination of chemotherapy and n-3 fatty acids was helpful in the curative as well as the palliative clinical setting (5), but a systematic review did not evaluate the balance of their cost-effectiveness against their utility (6). A number of studies have investigated cancer cell growth; however, only a limited number of studies have examined invasion and metastasis in prostate cancer, which exhibits an increasing prevalence. In the present study, the PC3 prostate cancer cell line was used, which is an androgen-independen...

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“…PI3K, PKC and PLC) that are altered in tumours and in inflammatory as well as in autoimmune diseases. One selective PIP5Ka inhibitor has recently been identified and proved effective in inhibiting advanced prostate cancer progression [166] and T lymphocyte activation (L. Tuosto, personal communication). Thus, more extensive investigation of the mechanisms regulating PIP5K recruitment, activation and regulation by its interacting partners may prove useful for the design of more selective targeted therapies for immune-based diseases.…”

Section: Discussionmentioning

confidence: 99%

The multifaceted role of PIP2 in leukocyte biology

Tuosto

Capuano

Muscolini

et al. 2015

Cell. Mol. Life Sci.

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Phosphatidylinositol 4,5-bisphosphate (PIP2) represents about 1 % of plasma membrane phospholipids and behaves as a pleiotropic regulator of a striking number of fundamental cellular processes. In recent years, an increasing body of literature has highlighted an essential role of PIP2 in multiple aspects of leukocyte biology. In this emerging picture, PIP2 is envisaged as a signalling intermediate itself and as a membrane-bound regulator and a scaffold of proteins with specific PIP2 binding domains. Indeed PIP2 plays a key role in several functions. These include directional migration in neutrophils, integrin-dependent adhesion in T lymphocytes, phagocytosis in macrophages, lysosomes secretion and trafficking at immune synapse in cytolytic effectors and secretory cells, calcium signals and gene transcription in B lymphocytes, natural killer cells and mast cells. The coordination of these different aspects relies on the spatio-temporal organisation of distinct PIP2 pools, generated by the main PIP2 generating enzyme, phosphatidylinositol 4-phosphate 5-kinase (PIP5K). Three different isoforms of PIP5K, named α, β and γ, and different splice variants have been described in leukocyte populations. The isoform-specific coupling of specific isoforms of PIP5K to different families of activating receptors, including integrins, Fc receptors, toll-like receptors and chemokine receptors, is starting to be reported. Furthermore, PIP2 is turned over by multiple metabolising enzymes including phospholipase C (PLC) γ and phosphatidylinositol 3-kinase (PI3K) which, along with Rho family small G proteins, is widely involved in strategic functions within the immune system. The interplay between PIP2, lipid-modifying enzymes and small G protein-regulated signals is also discussed.

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The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer

Cited by 95 publications

References 41 publications

PIP5K1α inhibition as a therapeutic strategy for prostate cancer

PIP5K1α inhibition as a therapeutic strategy for prostate cancer

Inhibition of PC3 human prostate cancer cell proliferation, invasion and migration by eicosapentaenoic acid and docosahexaenoic acid

The multifaceted role of PIP2 in leukocyte biology

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