Modulation of cholinephosphotransferase activity in breast cancer cell lines by Ro5-4864, a peripheral benzodiazepine receptor agonist

Akech, Jacqueline; Roy, Somdutta Sinha; Das, Salil K.

doi:10.1016/j.bbrc.2005.05.071

Cited by 16 publications

(12 citation statements)

References 30 publications

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“…Classic TSPO ligands have been demonstrated to stimulate cell proliferation [11][12][13], to protect against apoptosis [14][15][16] and to facilitate apoptosis [17][18][19][20][21][22][23][24][25][26][27][28][29][30]. However, the effects of these TSPO ligands on cell death/life mechanisms may vary depending on the ligand concentration, the experimental setting and the type of cell populations.…”

Section: Introductionmentioning

confidence: 99%

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

et al. 2014

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Ligands addressed to the mitochondrial Translocator Protein (TSPO) have been suggested as cell death/life and steroidogenesis modulators. Thus, TSPO ligands have been proposed as drug candidates in several diseases; nevertheless, a correlation between their binding affinity and in vitro efficacy has not been demonstrated yet, questioning the specificity of the observed effects. Since drug-target residence time is an emerging parameter able to influence drug pharmacological features, herein, the interaction between TSPO and irDE-MPIGA, a covalent TSPO ligand, was investigated in order to explore TSPO control on death/life processes in a standardized glioblastoma cell setting. After 90 min irDE-MPIGA cell treatment, 25 nM ligand concentration saturated irreversibly all TSPO binding sites; after 24 h, TSPO de-novo synthesis occurred and about 40 % TSPO binding sites resulted covalently bound to irDE-MPIGA. During cell culture treatments, several dynamic events were observed: (a) early apoptotic markers appeared, such as mitochondrial membrane potential collapse (at 3 h) and externalization of phosphatidylserine (at 6 h); (b) cell viability was reduced (at 6 h), without cell cycle arrest. After digitonin-permeabilized cell suspension treatment, a modulation of mitochondrial permeability transition pore was evidenced. Similar effects were elicited by the reversible TSPO ligand PIGA only when applied at micromolar dose. Interestingly, after 6 h, irDE-MPIGA cell exposure restored cell survival parameters. These results highlighted the ligand-target residence time and the cellular setting are crucial parameters that should be taken into account to understand the drug binding affinity and efficacy correlation and, above all, to translate efficiently cellular drug responses from bench to bedside.

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Section: Introductionmentioning

confidence: 99%

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

et al. 2014

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“…Previous studies have shown up-regulation of CHPT1 mRNA levels and activity in human breast cancer cells compared to normal mammary epithelial cells (48,49). Furthermore, the PCho/GPC ratio has been associated with malignant transformation (36,50).…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor α Promotes Breast Cancer by Reprogramming Choline Metabolism

et al. 2016

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Estrogen receptor α (ERα) is a key regulator of breast growth and breast cancer development.Here we report how ERα impacts these processes by reprogramming metabolism in malignant breast cells. We employed an integrated approach, combining genome-wide mapping of chromatin-bound ERα with estrogen-induced transcript and metabolic profiling, to demonstrate that ERα reprograms metabolism upon estrogen stimulation, including changes in aerobic glycolysis, nucleotide and amino acid synthesis and choline (Cho) metabolism. Cho phosphotransferase CHPT1, identified as a direct ERα-regulated gene, was required for estrogen-induced effects on Cho metabolism including increased phosphatidylcholine (PtdCho) synthesis. CHPT1 silencing inhibited anchorage-independent growth and cell proliferation, also suppressing early-stage metastasis of tamoxifen (TMX)-resistant breast cancer cells in a zebrafish xenograft model. Our results showed that ERα promotes metabolic alterations in breast cancer cells mediated by its target CHPT1, which this study implicates as a candidate therapeutic target.4

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“…Malignant neoplasm is characterized by its ability to invade and metastasize to other locations in the body (Akech et al, 2005). Malignant breast tumors are primarily featured by cell proliferation, tumor invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…PC, together with other phospholipids like phosphatidylserine, phosphatidylethanolamine, fatty acids and cholesterol, forms the lipid bilayer. Regulation of PC metabolism is one of the vital aspects of the cell cycle with implications in the control of cell proliferation as well as in apoptosis (Akech et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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Breast cancer is associated with an increase in the activity and expression of cholinephosphotransferase in rats

et al. 2008

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Modulation of cholinephosphotransferase activity in breast cancer cell lines by Ro5-4864, a peripheral benzodiazepine receptor agonist

Cited by 16 publications

References 30 publications

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

Estrogen Receptor α Promotes Breast Cancer by Reprogramming Choline Metabolism

Breast cancer is associated with an increase in the activity and expression of cholinephosphotransferase in rats

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