Choline Kinase Alpha (CHKα) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors

Mazarico, José M.; Lobo, Víctor J. Sánchez-Arévalo; Favicchio, Rosy; Greenhalf, William; Costello, Eithne; Pau, Enrique Carrillo de Santa; Marqués, Miriam; Lacal, Juan Carlos; Aboagye, Eric O.; Real, Francisco X.

doi:10.1158/1535-7163.mct-15-0214

Cited by 27 publications

(31 citation statements)

References 30 publications

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“…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. This conclusion, supported by the insensitivity of catalytically-inactive mutant CHKA2 D306A transformed cells to EGF-stimulated growth [39], contrasts the substantial literature demonstrating anti-proliferative effect of diverse small molecule CHKA ATP-, choline- and mixed-site binders on cell viability under unrestricted-growth media conditions and in mice [29, 40–44]. The hypothesis neither incorporates drug resistance possibilities, nor importantly the ability of the compounds to rapidly deplete phosphatidylcholine without significant regeneration.…”

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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“…впервые предложили использовать ингибиторы CHKα в качестве потенциальной противоопухолевой терапии [15]. На сегодняшний день существуют несколько поколений ингибиторов ХКα (MN58b, TCD-717) [7,15,16]. Радиоизотопное мечение холина дает возможность использовать его в качестве ПЭТ-индикатора.…”

Section: обоснованиеunclassified

“…В то же время оценка выраженности экспрессии ХКα с помощью иммуногистохимического (ИГХ) метода зарекомендовала себя при анализе образцов тканей опухолей молочной железы, легких и предстательной железы [21][22]. Ряд исследователей связывают степень и характер экспрессии ХКα с прогнозом заболевания [12,14,16]. Большинство из них склонны расценивать гиперэкспрессию ХКα, как неблагоприятный прогностический фактор [12,14,23].…”

Section: обоснованиеunclassified

“…При проведении ИГХ исследования мы выявили преимущественно цитоплазматическую реакцию с антителами к ХКα, в 3 случаяхмембранную. Однако ряд исследователей отмечали и учитывали не только цитоплазматическое окрашивание, но и ядерное [16][17][18][19][20][21][22][23][24][25]. Contractor K и соавт.…”

Section: обсуждение основного результата исследованияunclassified

“…Mazarico JM и соавт. сообщают о ядерном окрашивании в 43% (всего 96 пациентов) потоковых аденокарцином поджелудочной железы, что в приведенной работе было связано с более благоприятным прогнозом [16]. Феномен наличия ядерной экспрессии ХКα еще не до конца изучен.…”

Section: обсуждение основного результата исследованияunclassified

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Evaluation of the metabolism properties of choline kinase alpha in neoplasms of the parathyroid glands. A pilot study

et al. 2019

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BACKGROUND: Primary hyperparathyroidism (PHPT) is a widespread endocrine disease characterized by excessive production of parathyroid hormone (PTH) due to parathyroid gland hyperplasia (PGH) or tumor lesions (adenoma or cancer of the parathyroid gland (PG) in 80% and 15% of cases respectively). Choline kinase alpha (XK) overexpression is described in tumors of different localization, but there is no data on its expression in PG tumors. AIMS: To study the character of XK expression in PG neoplasms and its relationship with clinical, laboratory, and visualization characteristics (positron emission tomography combined with computed tomography (PET/CT) with 18Ffluorocholine (18FFC)). MATERIALS AND METHODS: The material for the study was based on tissue samples from 10 patients of 3470 years old (Me = 61.5; [48; 66]), with a laboratoryconfirmed diagnosis of PHT. An immunohistochemical study (IHC) was carried out on materials from 2 patients with hyperplasia of the main cells, from 5 patients with adenoma of PG, from 1 patient with atypical adenoma and 1 with carcinoma of PG; in 1 case the metastasis of cancer of the neck with lymph node was examined. RESULTS: The expression of XK is spotted in all types of PG cells (chief cells: active and inactive forms), transitional forms between the chief cells and oxyphil; oxyphil cells, but it was most intense in active chief cells. The expression of XK was observed in neoplasms of PG of various degrees of malignancy. In the most numerous group of PG formations with a favorable prognosis (11 samples from 7 patients), no statistically significant correlation (p 0.05) was obtained between the intensity expression of the XK, of the PTH and the proliferative activity index Ki67, the level of radiopharmaceutical accumulation in PET/CT with 18FFC (SUVmax) and laboratory data (PTH, Ca, Ca++). CONCLUSIONS: In the majority of investigated cases, moderate and intensive expression of the XK was detected in PG cells. A small amount of studied cases does not allow us to identify the connection between the intensity of XK expression and the malignant potential for the formation of PG.

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Crosstalk of FGFR1 signaling and choline metabolism promotes cell proliferation and survival in prostate cancer cells

Fan

Pan

et al. 2022

Intl Journal of Cancer

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The acquisition of ectopic type I fibroblast growth factor receptor (FGFR1) is a common feature of prostate cancer (PCa), the most frequently diagnostic cancer in men.However, how ectopic FGFR1 contributes to PCa progression is not well understood.In our study we showed that ablation of FGFR1 in DU145 human PCa cells changed the cell metabolite profile. Among the changes, the choline metabolism profile was the most significantly altered by FGFR1 ablation. Detailed characterization revealed that ablation of FGFR1 altered expression of multiple choline metabolism enzymes.Among the changes of FGFR1-regulated choline metabolic enzymes, downregulation of choline kinase α (CHKA) is the most prominent changes, which phosphorylates free choline to phosphocholine. Ablation of FGFR1 blunted the activity of choline to promote cell proliferation and survival. Furthermore, depletion of CHKA compromised FGF signaling activity in DU145 cells. We also first time demonstrated that FGFR1 formed complex with CHKA, suggesting that FGFR1 regulated CHKA at the posttranslational level. Together with the previous report that ectopic FGFR1 contributes to PCa progression and metastasis, our results here unravel a novel mechanism by which FGFR1 promotes PCa progression by dysregulating choline metabolism, and that the crosstalk between FGFR1-choline metabolism can be a potential target for managing PCa progression.

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Choline Kinase Alpha (CHKα) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors

Cited by 27 publications

References 30 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

Evaluation of the metabolism properties of choline kinase alpha in neoplasms of the parathyroid glands. A pilot study

Crosstalk of FGFR1 signaling and choline metabolism promotes cell proliferation and survival in prostate cancer cells

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