PIP5K1α inhibition as a therapeutic strategy for prostate cancer

Drake, Justin M.; Huang, Jiaoti

doi:10.1073/pnas.1413363111

Cited by 11 publications

(11 citation statements)

References 21 publications

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“…The recent revelation that the PIP 5-kinase isoform PIP5K1α can mediate TGN-endosome carrier formation is very interesting in light of the emerging importance of this this enzyme in malignant disease. 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).…”

Section: Pip5k1α − a Pi4p 5-kinase With Links To Golgi Exit And Cancermentioning

confidence: 99%

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

Waugh

2019

Biochemical Journal

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Phosphatidylinositol 4-phosphate (PI4P) is a membrane glycerophospholipid and a major regulator of the characteristic appearance of the Golgi complex as well as its vesicular trafficking, signalling and metabolic functions. Phosphatidylinositol 4-kinases, and in particular the PI4KIIIβ isoform, act in concert with PI4P to recruit macromolecular complexes to initiate the biogenesis of trafficking vesicles for several Golgi exit routes. Dysregulation of Golgi PI4P metabolism and the PI4P protein interactome features in many cancers and is often associated with tumour progression and a poor prognosis. Increased expression of PI4P-binding proteins, such as GOLPH3 or PITPNC1, induces a malignant secretory phenotype and the release of proteins that can remodel the extracellular matrix, promote angiogenesis and enhance cell motility. Aberrant Golgi PI4P metabolism can also result in the impaired post-translational modification of proteins required for focal adhesion formation and cell–matrix interactions, thereby potentiating the development of aggressive metastatic and invasive tumours. Altered expression of the Golgi-targeted PI 4-kinases, PI4KIIIβ, PI4KIIα and PI4KIIβ, or the PI4P phosphate Sac1, can also modulate oncogenic signalling through effects on TGN-endosomal trafficking. A Golgi trafficking role for a PIP 5-kinase has been recently described, which indicates that PI4P is not the only functionally important phosphoinositide at this subcellular location. This review charts new developments in our understanding of phosphatidylinositol 4-kinase function at the Golgi and how PI4P-dependent trafficking can be deregulated in malignant disease.

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Section: Pip5k1α − a Pi4p 5-kinase With Links To Golgi Exit And Cancermentioning

confidence: 99%

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

Waugh

2019

Biochemical Journal

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“…Loss or inactivation of the negative regulator for PI3K/Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), mutations in PI3K itself, and hyperactivation of Akt have been connected with chemoresistance in CRPC [ 405 , 406 , 407 ]. For instance, CRPC cells resistant to DTX were treated with the bioactive dietary flavonoid quercetin and DTX, which increased apoptosis and sensitivity to DTX by reducing the expression of phosphorylated Akt [ 402 , 408 ].…”

Section: Taxane Resistance In Prostate Cancermentioning

confidence: 99%

Mechanisms of Taxane Resistance

Maloney

Hoover

Morejon-Lasso

et al. 2020

Cancers

126

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The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug–inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome.

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“…It is predominantly located close to the inner leaflet of the plasma membrane, and its enzymatic function is to convert phosphatidylinositol 4-phosphate (PIP) to phosphatidylinositol 4,5-bisphosphate (PIP 2 ). We previously reported the discovery of ISA-2011B, a PIP5K1α inhibitor that selectively inhibited prostate cancer growth and invasion by targeting PI3K/AKT pathways [ 16 , 17 , 18 ]. PIP5K1α acts upstream of AKT [ 16 , 19 ], one of the most frequently altered proteins in human cancers.…”

Section: Introductionmentioning

confidence: 99%

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

Karlsson

Larsson

Miftakhova

et al. 2020

Cancers

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Cancer cells facilitate growth and metastasis by using multiple signals from the cancer-associated microenvironment. However, it remains poorly understood whether prostate cancer (PCa) cells may recruit and utilize bone marrow cells for their growth and survival. Furthermore, the regulatory mechanisms underlying interactions between PCa cells and bone marrow cells are obscure. In this study, we isolated bone marrow cells that mainly constituted populations that were positive for CD11b and Gr1 antigens from xenograft PC-3 tumor tissues from athymic nu/nu mice. We found that the tumor-infiltrated cells alone were unable to form tumor spheroids, even with increased amounts and time. By contrast, the tumor-infiltrated cells together with PCa cells formed large numbers of tumor spheroids compared with PCa cells alone. We further utilized xenograft athymic nu/nu mice bearing bone metastatic lesions. We demonstrated that PCa cells were unable to survive and give rise to colony-forming units (CFUs) in media that were used for hematopoietic cell colony-formation unit (CFU) assays. By contrast, PC-3M cells survived when bone marrow cells were present and gave rise to CFUs. Our results showed that PCa cells required bone marrow cells to support their growth and survival and establish bone metastasis in the host environment. We showed that PCa cells that were treated with either siRNA for PIP5K1α or its specific inhibitor, ISA-2011B, were unable to survive and produce tumor spheroids, together with bone marrow cells. Given that the elevated expression of PIP5K1α was specific for PCa cells and was associated with the induced expression of VEGF receptor 2 in PCa cells, our findings suggest that cancer cells may utilize PIP5K1α-mediated receptor signaling to recruit growth factors and ligands from the bone marrow-derived cells. Taken together, our study suggests a new mechanism that enables PCa cells to gain proliferative and invasive advantages within their associated host microenvironment. Therapeutic interventions using PIP5K1α inhibitors may not only inhibit tumor invasion and metastasis but also enhance the host immune system.

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PIP5K1α inhibition as a therapeutic strategy for prostate cancer

Cited by 11 publications

References 21 publications

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

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

Mechanisms of Taxane Resistance

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

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