Hint2, A Mitochondrial Apoptotic Sensitizer Down-Regulated in Hepatocellular Carcinoma

Martin, Juliette; Magnino, Fabrice; Schmidt, Karin; Piguet, Anne Christine; Lee, Ju Seog; Semela, David; St‐Pierre, Marie V.; Ziemiecki, Andrew; Cassio, Doris; Brenner, Charles; Thorgeirsson, Snorri S.; Dufour, Jean–François

doi:10.1053/j.gastro.2006.03.024

Cited by 58 publications

(58 citation statements)

References 35 publications

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“…We have shown low expression of HINT2 in endometrial cancer cells compared with control cells and expression of HINT2 was upregulated by progesterone and calcitriol treatment. These results are in agreement with a study suggesting that HINT2 overexpression sensitizes hepatocellular carcinoma to apoptosis (57).…”

Section: Discussionsupporting

confidence: 93%

Progesterone Enhances Calcitriol Antitumor Activity by Upregulating Vitamin D Receptor Expression and Promoting Apoptosis in Endometrial Cancer Cells

Lee

Teng

Nguyen

et al. 2013

Cancer Prevention Research

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Human studies suggest that progesterone and calcitriol may prove beneficial in preventing or inhibiting oncogenesis, but the underlying mechanism is not fully understood. The current study investigates the effects of progesterone, calcitriol, and their combination on immortalized human endometrial epithelial cells and endometrial cancer cells and identifies their targets of action. Combination treatment with both agents enhanced vitamin D receptor expression and inhibited cell proliferation through caspase-3 activation and induction of G 0 -G 1 cell-cycle arrest with associated downregulation of cyclins D1 and D3 and p27 induction. We used mass spectrometry-based proteomics to measure protein abundance differences between calcitriol-, progesterone-, or combination-exposed endometrial cells. A total of 117 proteins showed differential expression among these three treatments. Four proteins were then selected for validation studies: histone H1.4 (HIST1H1E), histidine triad nucleotide-binding protein 2 (HINT2), IFN-induced, double-stranded RNA-activated protein kinase (EIF2AK2), and Bcl-2-associated X protein (BAX). Abundance levels of selected candidates were low in endometrial cancer cell lines versus the immortalized endometrial epithelial cell line. All four proteins displayed elevated expression in cancer cells upon exposure to calcitriol, progesterone, or the combination. Further BAX analysis through gain-or loss-of-function experiments revealed that upregulation of BAX decreased cell proliferation by changing the BAX:BCL-2 ratio. Knockdown of BAX attenuated progesterone-and calcitriol-induced cell growth inhibition. Our results showed that progesterone and calcitriol upregulate the expression of BAX along with other apoptosis-related proteins, which induce inhibition of endometrial cancer cell growth by apoptosis and cell-cycle arrest. Cancer Prev Res; 6(7); 731-43. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 93%

Progesterone Enhances Calcitriol Antitumor Activity by Upregulating Vitamin D Receptor Expression and Promoting Apoptosis in Endometrial Cancer Cells

Lee

Teng

Nguyen

et al. 2013

Cancer Prevention Research

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“…BCATm KO was also Tables S1-S3). Hint1 appears to regulate proteasomal degradation of proteins by the SKP2-CUL1-F-box protein-E3 ubiquitin-protein ligase complex, whereas the mitochondrial isoform, Hint2, has been described as an apoptotic sensitizer (16,57). Increased expression of two genes that are linked to positive regulation of apoptosis, cytochrome C somatic (Cycs) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Bbip3, the most highly expressed member of this family in muscle), were also increased (Supplementary Tables S1-S2, notably no caspase genes were affected though).…”

Section: Resultsmentioning

confidence: 99%

Global deletion ofBCATmincreases expression of skeletal muscle genes associated with protein turnover

Lynch

Kimball

et al. 2015

Physiological Genomics

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Lynch CJ, Kimball SR, Xu Y, Salzberg AC, Kawasawa YI. Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover. Physiol Genomics 47: 569-580, 2015. First published September 8, 2015 doi:10.1152/physiolgenomics.00055.2015.-Consumption of a protein-containing meal by a fasted animal promotes protein accretion in skeletal muscle, in part through leucine stimulation of protein synthesis and indirectly through repression of protein degradation mediated by its metabolite, ␣-ketoisocaproate. Mice lacking the mitochondrial branched-chain aminotransferase (BCATm/Bcat2), which interconverts leucine and ␣-ketoisocaproate, exhibit elevated protein turnover. Here, the transcriptomes of gastrocnemius muscle from BCATm knockout (KO) and wildtype mice were compared by next-generation RNA sequencing (RNA-Seq) to identify potential adaptations associated with their persistently altered nutrient signaling. Statistically significant changes in the abundance of 1,486/ϳ39,010 genes were identified. Bioinformatics analysis of the RNA-Seq data indicated that pathways involved in protein synthesis [eukaryotic initiation factor (eIF)-2, mammalian target of rapamycin, eIF4, and p70S6K pathways including 40S and 60S ribosomal proteins], protein breakdown (e.g., ubiquitin mediated), and muscle degeneration (apoptosis, atrophy, myopathy, and cell death) were upregulated. Also in agreement with our previous observations, the abundance of mRNAs associated with reduced body size, glycemia, plasma insulin, and lipid signaling pathways was altered in BCATm KO mice. Consistently, genes encoding anaerobic and/or oxidative metabolism of carbohydrate, fatty acids, and branched chain amino acids were modestly but systematically reduced. Although there was no indication that muscle fiber type was different between KO and wild-type mice, a difference in the abundance of mRNAs associated with a muscular dystrophy phenotype was observed, consistent with the published exercise intolerance of these mice. The results suggest transcriptional adaptations occur in BCATm KO mice that along with altered nutrient signaling may contribute to their previously reported protein turnover, metabolic and exercise phenotypes.

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“…Our overexpression experiments indicated that HINT2 but not HINT3 was also able to catalyze the deamination reaction. However, it is likely that HINT1 is the major enzyme for GS-6620 activation, since HINT2 is a mitochondrial enzyme (21,22). The monophosphate metabolite must be phosphorylated to the active triphosphate form, GS-441326, by cellular nucleotide kinases.…”

Section: Discussionmentioning

confidence: 99%

Metabolism and Pharmacokinetics of the Anti-Hepatitis C Virus Nucleotide Prodrug GS-6620

Murakami

Wang

Babusis

et al. 2014

Antimicrob Agents Chemother

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The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with L-alanine-isopropyl ester and phenol moieties attached to the 5=-phosphate that release the nucleoside monophosphate in hepatocytes and a 3=-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equivalent surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be critical to the effectiveness of GS-6620 in nonclinical species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concentration. Higher rates of metabolism were observed at lower concentrations that were unable to saturate intestinal efflux transporters. In first-in-human clinical trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3=-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metabolism and relatively poor oral absorption in humans.A pproximately 170 million people worldwide are infected by the hepatitis C virus (HCV), and nearly 2% of the U.S. population is estimated to have HCV (1). HCV is a major health issue since approximately 15 to 35% of those who are chronically infected will develop cirrhosis and 1 to 3% will progress to hepatocellular carcinoma over 30 years (2). Currently, the recently approved protease inhibitors (boceprevir and telaprevir) are used in combination with pegylated interferon alpha plus ribavirin (PEG-RBV) for the treatment of chronic HCV infection. While these treatments show improved response rates and the potential for shorter duration of treatment over PEG-RBV alone, they lack efficacy against genotypes other than genotype 1, require thricedaily dosing, and cause additional side effects from the new directacting antivirals on top of the already-challenging tolerability profile of PEG-RBV. Therefore, there is a need for more potent anti-HCV compounds with improved clinical efficacy and greater tolerability in order to more broadly address the unmet medical needs of those with chronic HCV infection. Combinations of antiviral agents targeting viral proteins essential to HCV replication have the potential to achieve increased clinical efficacy across HCV genotypes, ...

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Hint2, A Mitochondrial Apoptotic Sensitizer Down-Regulated in Hepatocellular Carcinoma

Abstract: Background & Aims: Hints, Histidine triad nucleotide-binding proteins, are adenosine monophosphate-lysine hydrolases of uncertain biological function. Here we report the characterization of human Hint2.

Cited by 58 publications

References 35 publications

Progesterone Enhances Calcitriol Antitumor Activity by Upregulating Vitamin D Receptor Expression and Promoting Apoptosis in Endometrial Cancer Cells

Progesterone Enhances Calcitriol Antitumor Activity by Upregulating Vitamin D Receptor Expression and Promoting Apoptosis in Endometrial Cancer Cells

Global deletion ofBCATmincreases expression of skeletal muscle genes associated with protein turnover

Metabolism and Pharmacokinetics of the Anti-Hepatitis C Virus Nucleotide Prodrug GS-6620

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