Choline kinase-α protein and phosphatidylcholine but not phosphocholine are required for breast cancer cell survival

Mori, Noriko; Wildes, Flonné; Kakkad, Samata; Jacob, Desmond; Solaiyappan, Meiyappan; Glunde, Kristine; Bhujwalla, Zaver M.

doi:10.1002/nbm.3429

Cited by 30 publications

(37 citation statements)

References 49 publications

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“…It should be noted, however, that using a novel CHKA inhibitor, V-11–0711 [37], two independent laboratories have shown that drug-induced reductions of steady state PCho occurring after 24 h in HeLa and MDA-MB-231 were not sufficient to decrease cell viability, compared to CHKA RNAi [37, 38]; cell viability was lost only in SUM149 cells at similar drug concentrations. The groups infer that it is the depletion of CHKA protein - acting through non-catalytic functions [39] - but not inhibition of CHKA catalytic activity that is able to decrease cell survival.…”

Section: Discussionmentioning

confidence: 99%

The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth

et al. 2016

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The glycerophospholipid phosphatidylcholine is the most abundant phospholipid species of eukaryotic membranes and essential for structural integrity and signaling function of cell membranes required for cancer cell growth. Inhibition of choline kinase alpha (CHKA), the first committed step to phosphatidylcholine synthesis, by the selective small-molecule ICL-CCIC-0019, potently suppressed growth of a panel of 60 cancer cell lines with median GI50 of 1.12 μM and inhibited tumor xenograft growth in mice. ICL-CCIC-0019 decreased phosphocholine levels and the fraction of labeled choline in lipids, and induced G1 arrest, endoplasmic reticulum stress and apoptosis. Changes in phosphocholine cellular levels following treatment could be detected non-invasively in tumor xenografts by [18F]-fluoromethyl-[1,2–2H4]-choline positron emission tomography. Herein, we reveal a previously unappreciated effect of choline metabolism on mitochondria function. Comparative metabolomics demonstrated that phosphatidylcholine pathway inhibition leads to a metabolically stressed phenotype analogous to mitochondria toxin treatment but without reactive oxygen species activation. Drug treatment decreased mitochondria function with associated reduction of citrate synthase expression and AMPK activation. Glucose and acetate uptake were increased in an attempt to overcome the metabolic stress. This study indicates that choline pathway pharmacological inhibition critically affects the metabolic function of the cell beyond reduced synthesis of phospholipids.

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Section: Discussionmentioning

confidence: 99%

The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth

et al. 2016

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“…18 F and 11 C choline PET tracers are useful for identifying ChoK inhibition [28], but choline tracer accumulation can be affected by choline transport inhibitors [29, 30] which have known toxicities [31]. In addition, recent reports have shown that ChoKα protein scaffolding, rather than the enzymatic function, may be critical for supporting cell viability [21, 32, 33]. Miyake and Parsons reported a c-Src-dependent link between ChoKα and EGFR [32].…”

Section: Introductionmentioning

confidence: 99%

“…Miyake and Parsons reported a c-Src-dependent link between ChoKα and EGFR [32]. More recent studies showed that small molecule non- symmetric ChoKα inhibitors with low nM IC 50 s could substantially reduce the metabolic product PC but only cause reversible growth arrest with no effects on cell viability [21, 33]. Thus further development of fluorescence-based imaging strategies that report on enzyme expression rather than enzyme activity is needed.…”

Section: Introductionmentioning

confidence: 99%

Near infrared fluorescent imaging of choline kinase alpha expression and inhibition in breast tumors

et al. 2017

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Choline kinase alpha (ChoKα) overexpression is associated with an aggressive tumor phenotype. ChoKα inhibitors induce apoptosis in tumors, however validation of their specificity is difficult in vivo. We report the use of optical imaging to assess ChoKα status in cells and in vivo using JAS239, a carbocyanine-based ChoKα inhibitor with inherent near infrared fluorescence. JAS239 attenuated choline phosphorylation and viability in a panel of human breast cancer cell lines. Antibody blockade prevented cellular retention of JAS239 indicating direct interaction with ChoKα independent of the choline transporters and catabolic choline pathways. In mice bearing orthotopic MCF7 breast xenografts, optical imaging with JAS239 distinguished tumors overexpressing ChoKα from their empty vector counterparts and delineated tumor margins. Pharmacological inhibition of ChoK by the established inhibitor MN58b led to a growth inhibition in 4175-Luc+ tumors that was accompanied by concomitant reduction in JAS239 uptake and decreased total choline metabolite levels as measured using magnetic resonance spectroscopy. At higher therapeutic doses, JAS239 was as effective as MN58b at arresting tumor growth and inducing apoptosis in MDA-MB-231 tumors, significantly reducing tumor choline below baseline levels without observable systemic toxicity. These data introduce a new method to monitor therapeutically effective inhibitors of choline metabolism in breast cancer using a small molecule companion diagnostic.

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“…In a translational approach, we applied the CHKα-inhibitor V-11-0711 (Vertex Pharmaceuticals Incorporated) on GBM cells and tested subsequent alterations in geno- and phenotype. V-11-0711 has been shown to specifically suppress CHKα catalytic activity in breast cancer and HeLa cells [32, 33]. …”

Section: Resultsmentioning

confidence: 99%

“…Given our evidences from the genetic studies that CHKα controls mesenchymal differentiation, we tested the effect of compound based CHKα inhibition using the CHKα inhibitor V-11-0711 which recently has been shown to selectively inhibit CHKα activity [32, 33]. Analysis of metabolic extracts with 1 H NMR spectroscopy proved the enzyme inhibiting capability of V-11-0711 in GBM cells as we did not detect any CHKα product - PC at 3.22 ppm – after drug exposure (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

et al. 2016

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Glioblastoma (GBM) is the most malignant brain tumor with very limited therapeutic options. Standard multimodal treatments, including surgical resection and combined radio-chemotherapy do not target the most aggressive subtype of glioma cells, brain tumor stem cells (BTSCs). BTSCs are thought to be responsible for tumor initiation, progression, and relapse. Furthermore, they have been associated with the expression of mesenchymal features as a result of epithelial-mesenchymal transition (EMT) thereby inducing tumor dissemination and chemo resistance. Using high resolution proton nuclear magnetic resonance spectroscopy (1H NMR) on GBM cell cultures we provide evidence that the expression of well-known EMT activators of the ZEB, TWIST and SNAI families and EMT target genes N-cadherin and VIMENTIN is associated with aberrant choline metabolism. The cholinic phenotype is characterized by high intracellular levels of phosphocholine and total choline derivatives and was associated with malignancy in various cancers. Both genetic and pharmacological inhibition of the cardinal choline metabolism regulator choline kinase alpha (CHKα) significantly reduces the cell viability, invasiveness, clonogenicity, and expression of EMT associated genes in GBM cells. Moreover, in some cell lines synergetic cytotoxic effects were observed when combining the standard of care chemotherapeutic temozolomide with the CHKα inhibitor V-11-0711. Taken together, specific inhibition of the enzymatic activity of CHKα is a powerful strategy to suppress EMT which opens the possibility to target chemo-resistant BTSCs through impairing their mesenchymal transdifferentiation. Moreover, the newly identified EMT-oncometabolic network may be helpful to monitor the invasive properties of glioblastomas and the success of anti-EMT therapy.

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Choline kinase-α protein and phosphatidylcholine but not phosphocholine are required for breast cancer cell survival

Cited by 30 publications

References 49 publications

The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth

The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth

Near infrared fluorescent imaging of choline kinase alpha expression and inhibition in breast tumors

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

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