Aberrant lipid metabolism as a therapeutic target in liver cancer

Pope, Evans D.; Kimbrough, ErinMarie O.; Vemireddy, Lalitha Padmanabha; Surapaneni, Phani Keerthi; Copland, John A.; Mody, Kabir

doi:10.1080/14728222.2019.1615883

Cited by 125 publications

(101 citation statements)

References 119 publications

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“…Indeed, CIC transport inhibition blocks tumor growth and its activity is increased in HCC [19,20]. Enzymes of de novo fatty acid synthesis including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase, and fatty acid synthase are also overexpressed in a wide variety of solid human tumors, including HCC [21]. Of note, citrate export represents a further protection of mitochondria from excessive glycolysis because any pyruvate entering TCA cycle is channeled into this way.…”

Section: Introductionmentioning

confidence: 99%

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

Todisco

Convertini

Iacobazzi

et al. 2019

Cancers

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Hepatocellular carcinoma (HCC) is a common malignancy. Despite progress in treatment, HCC is still one of the most lethal cancers. Therefore, deepening molecular mechanisms underlying HCC pathogenesis and development is required to uncover new therapeutic strategies. Metabolic reprogramming is emerging as a critical player in promoting tumor survival and proliferation to sustain increased metabolic needs of cancer cells. Among the metabolic pathways, the tricarboxylic acid (TCA) cycle is a primary route for bioenergetic, biosynthetic, and redox balance requirements of cells. In recent years, a large amount of evidence has highlighted the relevance of the TCA cycle rewiring in a variety of cancers. Indeed, aberrant gene expression of several key enzymes and changes in levels of critical metabolites have been observed in many solid human tumors. In this review, we summarize the role of the TCA cycle rewiring in HCC by reporting gene expression and activity dysregulation of enzymes relating not only to the TCA cycle but also to glutamine metabolism, malate/aspartate, and citrate/pyruvate shuttles. Regarding the transcriptional regulation, we focus on the link between NF-κB-HIF1 transcriptional factors and TCA cycle reprogramming. Finally, the potential of metabolic targets for new HCC treatments has been explored.

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Section: Introductionmentioning

confidence: 99%

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

Todisco

Convertini

Iacobazzi

et al. 2019

Cancers

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“…Metabolic reprogramming contributes to tumor development, metastasis and drug resistance. Therefore, others and we have proposed to exploit the metabolic liabilities to treat cancers [13,[37][38][39][40][41][42].…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Inhibitors Targeting Multi-UDP-hexose Pyrophosphorylases as Anticancer Agents

et al. 2020

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To minimize treatment toxicities, recent anti-cancer research efforts have switched from broad-based chemotherapy to targeted therapy, and emerging data show that altered cellular metabolism in cancerous cells can be exploited as new venues for targeted intervention. In this study, we focused on, among the altered metabolic processes in cancerous cells, altered glycosylation due to its documented roles in cancer tumorigenesis, metastasis and drug resistance. We hypothesize that the enzymes required for the biosynthesis of UDP-hexoses, glycosyl donors for glycan synthesis, could serve as therapeutic targets for cancers. Through structure-based virtual screening and kinetic assay, we identified a drug-like chemical fragment, GAL-012, that inhibit a small family of UDP-hexose pyrophosphorylases-galactose pyro-phosphorylase (GALT), UDP-glucose pyrophosphorylase (UGP2) and UDP-N-acetylglucosamine pyrophosphorylase (AGX1/UAP1) with an IC50 of 30 µM. The computational docking studies supported the interaction of GAL-012 to the binding sites of GALT at Trp190 and Ser192, UGP2 at Gly116 and Lys127, and AGX1/UAP1 at Asn327 and Lys407, respectively. One of GAL-012 derivatives GAL-012-2 also demonstrated the inhibitory activity against GALT and UGP2. Moreover, we showed that GAL-012 suppressed the growth of PC3 cells in a dose-dependent manner with an EC50 of 75 µM with no effects on normal skin fibroblasts at 200 µM. Western blot analysis revealed reduced expression of pAKT (Ser473), pAKT (Thr308) by 77% and 72%, respectively in the treated cells. siRNA experiments against the respective genes encoding the pyrophosphorylases were also performed and the results further validated the proposed roles in cancer growth inhibition. Finally, synergistic relationships between GAL-012 and tunicamycin, as well as bortezomib (BTZ) in killing cultured cancer cells were observed, respectively. With its unique scaffold and relatively small size, GAL-012 serves as a promising early chemotype for optimization to become a safe, effective, multi-target anti-cancer drug candidate which could be used alone or in combination with known therapeutics.

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“…We can assume that excess of С 3:0 and С 4:0 in cervical cancer lesion after incubation with propionate is caused not only by its exogenous inflow, but also by interconversions of SCFA, oxidation reaction of even-numbered (for butyric acid) and odd-numbered (for propionic acid) fatty acids, as well as by the possibility of preliminary formation of С 3:0 in tumor tissue from glucose. Such changes in malignant tissue are possibly caused by high energy status of tumor cells [11][12][13][14][15].…”

Section: Discussionmentioning

confidence: 99%

The Influence of Propionate on the Spectrum of Short-Chain Fatty Acids in Cervical Cells During Dis- and Neoplastic Transformation

Elena¹,

Tatyayna²,

Leonid³

et al. 2019

IJBSE

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Introduction. There is some data of the short-chain fatty acids (SCFA) participation in cancerogenesis. The cervical cancer is an "ideal" model for determining the molecular mechanisms underlying the development of cancer. The aim of study was to estimate the influence of propionate on the spectrum of SCFA in cervical cells during dis-and neoplastic transformation. Materials and methods of research. Materials of the study-cervical biopsy verified morphologically. Study groups: IA-the focus of the pretumor lesion of cervix; IB-paradisplastic cells; IIA-locus of cervical cancer; IIBparaneoplastic cells. The spectrum of fatty acids was analyzed before, after 24 hours incubation with 50 µmol/l propionic acid by the gas chromatography method. Methods of nonparametric statistics the Mann-Whitney test were used. Differences were considered statistically significant at p<0.05. Results of the study. The incubation of cervical cancer cells with propionate leads to an increase the level of propionate and butyrate. The incubation of "precancer", paraneoplastic and paradisplastic cells leads to an increase the levels of isobutyric, valeric and caproic acids against the background of a significant drop in the concentration of propionate and butyrate. Сonclusion. It can be concluded that the effect of propionate on the metabolism of fatty acids in the cervical epithelium of the studied samples is multidirectional and depends on the cell type. The dates indicate the modifications of SCFA in the cervical carcinogenesis.

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Aberrant lipid metabolism as a therapeutic target in liver cancer

Cited by 125 publications

References 119 publications

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

Discovery of Novel Inhibitors Targeting Multi-UDP-hexose Pyrophosphorylases as Anticancer Agents

The Influence of Propionate on the Spectrum of Short-Chain Fatty Acids in Cervical Cells During Dis- and Neoplastic Transformation

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