Choline kinase alpha—Putting the ChoK-hold on tumor metabolism

Arlauckas, Sean P.; Popov, Anatoliy V.; Delikatny, Edward J.

doi:10.1016/j.plipres.2016.03.005

Cited by 58 publications

(93 citation statements)

References 152 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Expanding interest in ChoKα inhibitors for cancer therapy has raised the need for rapid and reliable methods to validate these therapies in vivo [5]. There have been concerns with the reliability of RECIST measurement as a marker of treatment responsiveness [51].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Choline kinase alpha (ChoKα) has become the subject of intense interest for its utility as an oncogenic biomarker as well as an anticancer therapeutic target [1–5]. ChoKα catalyzes choline phosphorylation as an intermediate step in the synthesis of two abundant membrane phospholipids, phosphatidylcholine (PtdCho) and sphingomyelin.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Lipid synthesis is essential for cell growth, proliferation and differentiation, and although many mutations in oncogenes, such as KRAS and MYC, control lipid metabolism [156,157], few lipid enzymes have been reported to drive tumorigenesis [158]. Choline kinase α (CHKα), a key enzyme involved in choline metabolism, is a notable exception [159].…”

Section: Choline Metabolism Supports Emtmentioning

confidence: 99%

“…Aberrant choline metabolism has been observed in multiple cancers. An increasing amount of research has focused on the molecular mechanism underlying abnormal choline metabolism, providing potential targets in cancer therapy [158,160].…”

Section: Choline Metabolism Supports Emtmentioning

confidence: 99%

TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer

Wang

Dijke

Kostidis

et al. 2019

Cell. Mol. Life Sci.

183

144

View full text Add to dashboard Cite

Metastasis is the most frequent cause of death in cancer patients. Epithelial-to-mesenchymal transition (EMT) is the process in which cells lose epithelial integrity and become motile, a critical step for cancer cell invasion, drug resistance and immune evasion. The transforming growth factor-β (TGFβ) signaling pathway is a major driver of EMT. Increasing evidence demonstrates that metabolic reprogramming is a hallmark of cancer and extensive metabolic changes are observed during EMT. The aim of this review is to summarize and interconnect recent findings that illustrate how changes in glycolysis, mitochondrial, lipid and choline metabolism coincide and functionally contribute to TGFβ-induced EMT. We describe TGFβ signaling is involved in stimulating both glycolysis and mitochondrial respiration. Interestingly, the subsequent metabolic consequences for the redox state and lipid metabolism in cancer cells are found to be in favor of EMT as well. Combined we illustrate that a better understanding of the mechanistic links between TGFβ signaling, cancer metabolism and EMT holds promising strategies for cancer therapy, some of which are already actively being explored in the clinic.

show abstract

“…Interestingly, we found that overexpression of T3-buffering CRYM leads to a reduction in intracellular choline levels in PC3 cells. CHKA has a crucial role in phospholipid metabolism through catalyzing the choline phosphorylation to form phosphocholine, a phospholipid component of bilayers in cell membranes (25). Total choline expression has been shown to be elevated in PCa tissue as compared to healthy, age matched controls (26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

Thyroid and androgen receptor signaling are antagonized by CRYM in prostate cancer

Aksoy

Pěnčík

Hartenbach³

et al. 2019

Preprint

View full text Add to dashboard Cite

Highlights• Thyroid and androgen hormone driven pathways in prostate cancer (PCa) are antagonized by μ-Crystallin (CRYM).• [18F]fluoromethylcholine uptake and prognostic values in PCa correlate with CRYM protein levels.• Reduced CRYM expression predicts early biochemical recurrence (BCR) in PCa patients. AbstractAndrogen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3'-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidence indicates a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRa/TRb) in target tissues. We show in this study that low CRYM expression levels in PCa patient samples are associated with early BCR and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in PET/MRI imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3 and androgen-mediated signalling. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.

show abstract

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism

Cited by 58 publications

References 152 publications

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

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

TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer

Thyroid and androgen receptor signaling are antagonized by CRYM in prostate cancer

Contact Info

Product

Resources

About