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

Vignarajan, Soma; Xie, Chanlu; Mu, Yuguang; Sun, Yuting; Simanainen, Ulla; Sved, Paul; Liu, Tao; Dong, Qihan

doi:10.18632/oncotarget.2198

Cited by 20 publications

(13 citation statements)

References 42 publications

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“…Metabolites present in the 31 P-NMR spectrum from cancer cells include171819 the product of choline kinase (CK) and phospholipase C (PLC), phosphocholine (PCho) and the product of Phospholipase A2 (PLA2) glycerophosphocholine (GPC) from the breakdown of phosphatidylcholine. Studies20212223 have established that the activity of anabolic (CK) and catabolic (PLA2, PLC and PLD) phospholipid enzymes are regulated by the Akt/mTor pathway. Thus the expression and activity of choline kinase are controlled by a complex of which PI3K is a part2021.…”

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confidence: 99%

“…Thus the expression and activity of choline kinase are controlled by a complex of which PI3K is a part2021. Recent work has demonstrated that protein levels of PLA2 are regulated by Akt which inhibits PLA2 degradation22. A further peak evident in 31 P-NMR spectra of some tumours is the UDP-hexoses peak which includes resonances from UDP-glucose which is converted to glycogen by glycogen synthase.…”

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confidence: 99%

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Probing the PI3K/Akt/mTor pathway using 31P-NMR spectroscopy: routes to glycogen synthase kinase 3

Phyu¹,

Tseng²,

Fleming³

et al. 2016

Sci Rep

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Akt is an intracellular signalling pathway that serves as an essential link between cell surface receptors and cellular processes including proliferation, development and survival. The pathway has many downstream targets including glycogen synthase kinase3 which is a major regulatory kinase for cell cycle transit as well as controlling glycogen synthase activity. The Akt pathway is frequently up-regulated in cancer due to overexpression of receptors such as the epidermal growth factor receptor, or mutation of signalling pathway kinases resulting in inappropriate survival and proliferation. Consequently anticancer drugs have been developed that target this pathway. MDA-MB-468 breast and HCT8 colorectal cancer cells were treated with inhibitors including LY294002, MK2206, rapamycin, AZD8055 targeting key kinases in/associated with Akt pathway and the consistency of changes in 31P-NMR-detecatable metabolite content of tumour cells was examined. Treatment with the Akt inhibitor MK2206 reduced phosphocholine levels in MDA-MB-468 cells. Treatment with either the phosphoinositide-3-kinase inhibitor, LY294002 and pan-mTOR inhibitor, AZD8055 but not pan-Akt inhibitor MK2206 increased uridine-5′-diphosphate-hexose cell content which was suppressed by co-treatment with glycogen synthase kinase 3 inhibitor SB216763. This suggests that there is an Akt-independent link between phosphoinositol-3-kinase and glycogen synthase kinase3 and demonstrates the potential of 31P-NMR to probe intracellular signalling pathways.

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confidence: 99%

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confidence: 99%

Probing the PI3K/Akt/mTor pathway using 31P-NMR spectroscopy: routes to glycogen synthase kinase 3

Phyu¹,

Tseng²,

Fleming³

et al. 2016

Sci Rep

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“…Protein quantification, electrophoresis and western blotting were performed as previously described. 42 Antibodies (human specific) used were c-MYC (Abcam, Epitomics, Cambridge, UK, #1472-1), S62-phospho-c-MYC (ab51156), T58-phospho-c-MYC (ab28842) and GAPDH (ab128915) were obtained from Abcam Company (Cambridge, UK). Additional antibodies were phospho-Rb (Ser807/811) (#9308), ERK1/2 (137F5) (#4695), phospho-ERK1/2 (Thr202/Tyr204) (#4370), GSK3 β (27C10) (#9315) and phospho-GSK3 β (Ser 9) (#9323) purchased from Cell Signaling Technology (Danvers, MA, USA), FBXW7 (A301-721A) were obtained from Bethyl Laboratories (Montgomery, TX, USA) and α -tubulin (sc-5286) from Santa Cruz Biotechnology (Dallas, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…The color development was as previously described. 42 The sections were mounted using DPX for histological analysis.…”

Section: Methodsmentioning

confidence: 99%

Guttiferone K impedes cell cycle re-entry of quiescent prostate cancer cells via stabilization of FBXW7 and subsequent c-MYC degradation

et al. 2016

Cell Death Dis

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Cell cycle re-entry by quiescent cancer cells is an important mechanism for cancer progression. While high levels of c-MYC expression are sufficient for cell cycle re-entry, the modality to block c-MYC expression, and subsequent cell cycle re-entry, is limited. Using reversible quiescence rendered by serum withdrawal or contact inhibition in PTENnull/p53WT (LNCaP) or PTENnull/p53mut (PC-3) prostate cancer cells, we have identified a compound that is able to impede cell cycle re-entry through c-MYC. Guttiferone K (GUTK) blocked resumption of DNA synthesis and preserved the cell cycle phase characteristics of quiescent cells after release from the quiescence. In vehicle-treated cells, there was a rapid increase in c-MYC protein levels upon release from the quiescence. However, this increase was inhibited in the presence of GUTK with an associated acceleration in c-MYC protein degradation. The inhibitory effect of GUTK on cell cycle re-entry was significantly reduced in cells overexpressing c-MYC. The protein level of FBXW7, a subunit of E3 ubiquitin ligase responsible for degradation of c-MYC, was reduced upon the release from the quiescence. In contrast, GUTK stabilized FBXW7 protein levels during release from the quiescence. The critical role of FBXW7 was confirmed using siRNA knockdown, which impaired the inhibitory effect of GUTK on c-MYC protein levels and cell cycle re-entry. Administration of GUTK, either in vitro prior to transplantation or in vivo, suppressed the growth of quiescent prostate cancer cell xenografts. Furthermore, elevation of FBXW7 protein levels and reduction of c-MYC protein levels were found in the xenografts of GUTK-treated compared with vehicle-treated mice. Hence, we have identified a compound that is capable of impeding cell cycle re-entry by quiescent PTENnull/p53WT and PTENnull/p53mut prostate cancer cells likely by promoting c-MYC protein degradation through stabilization of FBXW7. Its usage as a clinical modality to prevent prostate cancer progression should be further evaluated.

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“…Proteins were extracted from the whole uterus from 20-week-old female mice and western blot was performed to measure PTEN, AKT, P-AKT, and p27 levels as previously described (Vignarajan et al 2014). The antibodies used were PTEN (138G6, Cell Signaling, 1:500), AKT (sc-8312, Santa Cruz Biotechnology, 1:500), P-AKT (sc-7985, Santa Cruz Biotechnology, 1:300), p27 (sc-528, Santa Cruz Biotechnology, 1:500), and B-actin (ab8229, Abcam, Cambridge, UK, 1:3000).…”

Section: Protein Extraction and Western Blotmentioning

confidence: 99%

Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer

Choi

Desai

Zheng

et al. 2015

Endocrine-Related Cancer

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Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERa expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P 4 ) is assumed protective in uterine cancers, serum P 4 was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.

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

Cited by 20 publications

References 42 publications

Probing the PI3K/Akt/mTor pathway using 31P-NMR spectroscopy: routes to glycogen synthase kinase 3

Probing the PI3K/Akt/mTor pathway using 31P-NMR spectroscopy: routes to glycogen synthase kinase 3

Guttiferone K impedes cell cycle re-entry of quiescent prostate cancer cells via stabilization of FBXW7 and subsequent c-MYC degradation

Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer

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