Pharmacological Targeting of the Integrated Protein Kinase B, Phosphatase and Tensin Homolog Deleted on Chromosome 10, and Transforming Growth Factor-β Pathways in Prostate Cancer

Assinder, Stephen J.; Dong, Qihan; Mangs, Helena; Richardson, Des R.

doi:10.1124/mol.108.053066

Cited by 7 publications

(3 citation statements)

References 110 publications

(125 reference statements)

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“…Actually, TGF-β and PI3K are involved in many cell lines. 43,44 It was reported that PI3K was activated by tyrosine kinase 45,46 and our results further verified that in CML, it was activated by tyrosine kinase induced TGF-β1. Following its recruitment to these receptors in the plasma membrane, PI3K is activated and phosphorylated to generate the second messenger PIP3, whose levels are tightly regulated by the action of phosphatases.…”

Section: Discussionsupporting

confidence: 86%

BCR/ABL oncogene-induced PI3K signaling pathway leads to chronic myeloid leukemia pathogenesis by impairing immuno-modulatory function of hemangioblasts

Fang

et al. 2015

Cancer Gene Ther

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An increasing number of studies indicate that during development, endothelial and hematopoietic cells derive from common progenitors named hemangioblasts that have important roles in the pathogenesis. This is particularly true in chronic myeloid leukemia (CML). Here, we isolated fetal liver kinase-1-positive (Flk1(+)) cells from CML patients and found they expressed BCR/ABL-specific CML oncogene. We examined their biological characteristics as well as immunological functions and further detected the possible molecular mechanism involved in the leukemia genesis. We showed that CML patient-derived Flk1(+)CD31(-)CD34(-) mesenchymal stem cells (MSCs) had normal morphology, phenotype and karyotype but appeared impaired immuno-modulatory function. The capacity of Flk1(+)CD31(-)CD34(-) MSCs from CML patients to inhibit T lymphocyte activation and proliferation was impaired in vitro. CML patient-derived MSCs have dampening immuno-modulatory functions, suggesting that the dysregulation of hematopoiesis and immune response might originate from MSCs rather than hematopoietic stem cells (HSCs). These Ph(+) putative CML hemangioblast upregulated TGF-β1 and resultantly activated matrix metalloproteinase-9 (MMP-9) to enhance s-KitL and s-ICAM-1 secretion, which activated c-kit(+) HSCs from the quiescent state to the proliferative state. Further studies showed that phosphatidylinositol-3 kinase (PI3K)/Akt/nuclear factor (NF)-κB signaling pathway was involved in CML pathogenesis. Flk1(+)CD31(-)CD34(-) MSCs that express BCR/ABL leukemia oncogene are hemangioblasts and they have a critical role in the progression of CML through PI3K/Akt/NF-κB signaling pathway.

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Section: Discussionsupporting

confidence: 86%

BCR/ABL oncogene-induced PI3K signaling pathway leads to chronic myeloid leukemia pathogenesis by impairing immuno-modulatory function of hemangioblasts

Fang

et al. 2015

Cancer Gene Ther

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“…Prostate cancer is a highly heterogeneous disease with many points of disruption in cell signalling (Assinder et al , 2009). Three such pathways are the tumourigenic phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), tumour-suppressive phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and transforming growth factor- β (TGF- β ) pathways (Assinder et al , 2008, 2009). Several points of integration appear to occur between these pathways, with N-myc downstream-regulated gene-1 (NDRG1) being a possible common point of cross-talk (Assinder et al , 2008, 2009).…”

mentioning

confidence: 99%

Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells

et al. 2013

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Background:Effective treatment of prostate cancer should be based on targeting interactions between tumour cell signalling pathways and key converging downstream effectors. Here, we determined how the tumourigenic phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), tumour-suppressive phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and transforming growth factor-β (TGF-β) pathways are integrated via the metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1). Moreover, we assessed how the novel anti-tumour agent, Dp44mT, may target these integrated pathways by increasing NDRG1 expression.Methods:Protein expression in Dp44mT-treated normal human prostate epithelial cells and prostate cancer cells (PC-3, DU145) was assessed by western blotting. The role of NDRG1 was examined by transfection using an NDRG1 overexpression vector or shRNA.Results:Dp44mT increased levels of tumour-suppressive PTEN, and decreased phosphorylation of ERK1/2 and SMAD2L, which are regulated by oncogenic Ras/MAPK signalling. Importantly, the effects of Dp44mT on NDRG1 and p-SMAD2L expression were more marked in prostate cancer cells than normal prostate epithelial cells. This may partly explain the anti-tumour selectivity of these agents. Silencing NDRG1 expression increased phosphorylation of tumourigenic AKT, ERK1/2 and SMAD2L and decreased PTEN levels, whereas NDRG1 overexpression induced the opposite effect. Furthermore, NDRG1 silencing significantly reduced the ability of Dp44mT to suppress p-SMAD2L and p-ERK1/2 levels.Conclusion:NDRG1 has an important role in mediating the tumour-suppressive effects of Dp44mT in prostate cancer via selective targeting of the PI3K/AKT, TGF-β and ERK pathways.

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“…Since both pAKT and cPLA 2 α levels are implicated in the prostate cancer, and an understanding of the integration of biochemical pathways involved in cancer progression is a key to the development of improved pharmacological treatment strategies for cancer [27, 28], we aimed to examine the relationship between the oncogenic protein and the lipid modifying enzyme. Specifically, we verified the concordance between pAKT and cPLA 2 α in prostate tissue of epithelial-specific PTEN -knockout mouse, and tested the hypothesis that pAKT plays a causal role in promoting cPLA 2 α expression in prostate cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Loss of PTEN stabilizes the lipid modifying enzyme cytosolic phospholipase A2α via AKT in prostate cancer cells

Vignarajan

Xie

et al. 2014

Oncotarget

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Aberrant increase in pAKT, due to a gain-of-function mutation of PI3K or loss-of-function mutation or deletion of PTEN, occurs in prostate cancer and is associated with poor patient prognosis. Cytosolic phospholipase A2α (cPLA2α) is a lipid modifying enzyme by catalyzing the hydrolysis of membrane arachidonic acid. Arachidonic acid and its metabolites contribute to survival and proliferation of prostate cancer cells. We examined whether AKT plays a role in promoting cPLA2α action in prostate cancer cells. We found a concordant increase in pAKT and cPLA2α levels in prostate tissue of prostate epithelial-specific PTEN-knockout but not PTEN-wide type mice. Restoration of PTEN expression or inhibition of PI3K action decreased cPLA2α expression in PTEN-mutated or deleted prostate cancer cells. An increase in AKT by Myr-AKT elevated cPLA2α protein levels, which could be diminished by inhibition of AKT phosphorylation without noticeable change in total AKT levels. pAKT levels had no influence on cPLA2α at mRNA levels but reduced cPLA2α protein degradation. Anti-AKT antibody co-immunoprecipitated cPLA2α and vice versa. Hence, AKT plays a role in enhancing cPLA2α protein stability in PTEN-null prostate cancer cells, revealing a link between oncogenic pathway and lipid metabolism.

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Pharmacological Targeting of the Integrated Protein Kinase B, Phosphatase and Tensin Homolog Deleted on Chromosome 10, and Transforming Growth Factor-β Pathways in Prostate Cancer

Cited by 7 publications

References 110 publications

BCR/ABL oncogene-induced PI3K signaling pathway leads to chronic myeloid leukemia pathogenesis by impairing immuno-modulatory function of hemangioblasts

BCR/ABL oncogene-induced PI3K signaling pathway leads to chronic myeloid leukemia pathogenesis by impairing immuno-modulatory function of hemangioblasts

Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells

Loss of PTEN stabilizes the lipid modifying enzyme cytosolic phospholipase A2α via AKT in prostate cancer cells

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