Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting

Xiong, Jie; Bian, Jin; Wang, L; Zhou, Jinhua; Y, Wang; Zhao, Yiming; Ll, Wu; Jj, Hu; B, Li; Sj, Chen; C, Yan; Wl, Zhao

doi:10.1038/bcj.2015.10

Cited by 40 publications

(45 citation statements)

References 33 publications

(38 reference statements)

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“…Knockdown of CHKA by RNAi has been demonstrated to induce differentiation and reduce proliferation [12, 40], prevent mitotic entry [8], selectively trigger cancer cell apoptosis [41], suppress migration and invasion [21, 22, 31], and sensitize cancer cells to chemotherapeutics [22, 42]. Consistently, pharmacological inhibitors of CHKA has also displayed antiproliferative, proapoptotic and antitumoral effects against multiple tumor-derived cancer cells as well as tumor xenografts [18, 23, 32, 43–46]. Indeed, one CHKA inhibitor, designated as TCD-717 or RSM-932A, has recently completed Phase I clinical trials for the treatment of advanced solid tumors (ClinicalTrial.gov Identifier: NCT01215864) [27].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma

Wang

Cai

et al. 2016

Oncotarget

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Aberrant expression of choline kinase alpha (CHKA) has been reported in a variety of human malignancies including colorectal carcinoma (CRC). However, the role of CHKA in the progression and prognosis of CRC remains unknown. In this study, we found that CHKA was frequently upregulated in CRC clinical samples and CRC-derived cell lines and was significantly correlated with lymph node metastasis (p = 0.028), TNM stage (p = 0.009), disease recurrence (p = 0.004) and death (p < 0.001). Survival analyses indicated that patients with higher CHKA expression had a significantly shorter disease-free survival (DFS) and disease-specific survival (DSS) than those with lower CHKA expression. Multivariate analyses confirmed that increased CHKA expression was an independent unfavorable prognostic factor for CRC patients. In addition, combination of CHKA with TNM stage was a more powerful predictor of poor prognosis than either parameter alone. Functional study demonstrated that knockdown of CHKA expression profoundly suppressed the growth and metastasis of CRC cells both in vitro and in vivo. Mechanistic investigation revealed that EGFR/PI3K/AKT pathway was essential for mediating CHKA function. In conclusion, our results provide the first evidence that CHKA contributes to tumor progression and metastasis and may serve as a novel prognostic biomarker and potential therapeutic target in CRC.

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Section: Discussionmentioning

confidence: 99%

Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma

Wang

Cai

et al. 2016

Oncotarget

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“…Through the tail vein of anesthetized mice, 18F-fluorodeoxyglucose (18F-FDG, 0.1 ml per injection with an activity of 5.5 MBq) was injected. PET/CT imaging was performed on an Inveon MM Platform (Siemens Preclinical Solutions, Knoxville, TN, USA) with 8.5 cm transaxial and 5.7 cm axial fields of view, as previously described 30 .…”

Section: Methodsmentioning

confidence: 99%

JAM-A overexpression is related to disease progression in diffuse large B-cell lymphoma and downregulated by lenalidomide

Xu¹,

Sun²,

Fang³

et al. 2017

Sci Rep

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Cancer stem cells play an important role on tumor progression. Biomarkers of stem cell property and their relationship to extranodal involvement of malignant lymphocytes are undefined in diffuse large B-cell lymphoma (DLBCL). Here we showed that junctional adhesion molecule-A (JAM-A) was highly expressed in DLBCL patients with multiple extranodal lesions. JAM-A maintained B-lymphoma cell stemness and was associated with cell invasion and epithelial-to-mesenchymal transition both in vitro and in vivo. As mechanism of action, JAM-A overexpression selectively activated transforming growth factor-β (TGF-β)/NODAL signaling, thereby enhanced B-lymphoma cell aggressiveness and induced extranodal involvement to mesoendoderm-derived organs in DLBCL. Lenalidomide downregulated JAM-A and downstream NODAL expression, resulting in inhibition of B-lymphoma cell invasion and epithelial-to-mesenchymal transition. In a murine xenograft model established with subcutaneous injection of JAM-A-overexpressing B-lymphoma cells, lenalidomide retarded tumor growth and prevented cell invasion to mesoendoderm-derived organs, consistent with the downregulation of JAM-A and NODAL expression. Collectively, these findings indicated that JAM-A was related to extranodal involvement in DLBCL through modulating TGF-β/NODAL signaling. Identified as a biomarker of stem cell property, JAM-A indicated the sensitivity of B-lymphoma cells to lenalidomide. Therapeutic targeting of JAM-A/NODAL axis could thus be a promising clinical strategy to impede tumor progression in DLBCL.

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“…Choline kinase is overexpressed in many tumors such as breast, lung, bladder, colon, prostate, ovary, and liver carcinomas 14 15 16 and recently elevated enzymatic activity has also been shown in T-lymphoma 17 . This increasing expression leads to abnormal choline metabolism, resulting in higher phosphocholine levels, which refer to a cholinic phenotype associated with oncogenesis and tumor progression 18 .…”

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confidence: 99%

Design, synthesis, crystallization and biological evaluation of new symmetrical biscationic compounds as selective inhibitors of human Choline Kinase α1 (ChoKα1)

Schiaffino-Ortega¹,

Baglioni²,

Mariotto

et al. 2016

Sci Rep

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A novel family of compounds derivative of 1,1′-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bispyridinium or –bisquinolinium bromide (10a-l) containing a pair of oxygen atoms in the spacer of the linker between the biscationic moieties, were synthesized and evaluated as inhibitors of choline kinase against a panel of cancer-cell lines. The most promising compounds in this series were 1,1′-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))bis(4-(dimethylamino)pyridinium) bromide (10a) and 1,1′-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bis(7-chloro-4-(pyrrolidin-1-yl)quinolinium) bromide (10l), which inhibit human choline kinase (ChoKα1) with IC50 of 1.0 and 0.92 μM, respectively, in a range similar to that of the previously reported biscationic compounds MN58b and RSM932A. Our compounds show greater antiproliferative activities than do the reference compounds, with unprecedented values of GI50 in the nanomolar range for several of the cancer-cell lines assayed, and more importantly they present low toxicity in non-tumoral cell lines, suggesting a cancer-cell-selective antiproliferative activity. Docking studies predict that the compounds interact with the choline-binding site in agreement with the binding mode of most previously reported biscationic compounds. Moreover, the crystal structure of ChoKα1 with compound 10a reveals that this compound binds to the choline-binding site and mimics HC-3 binding mode as never before.

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Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting

Cited by 40 publications

References 33 publications

Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma

Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma

JAM-A overexpression is related to disease progression in diffuse large B-cell lymphoma and downregulated by lenalidomide

Design, synthesis, crystallization and biological evaluation of new symmetrical biscationic compounds as selective inhibitors of human Choline Kinase α1 (ChoKα1)

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