High Glucose Modulates Antiproliferative Effect and Cytotoxicity of 5-Fluorouracil in Human Colon Cancer Cells

Ma, Yi‐Shing; Yang, I‐Ping; Tsai, Hsiang‐Lin; Huang, Ching‐Wen; Juo, Suh‐Hang Hank; Wang, Jaw‐Yuan

doi:10.1089/dna.2013.2161

Cited by 52 publications

(49 citation statements)

References 36 publications

(39 reference statements)

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“…Foods with high glycemic load are most closely correlated with higher recurrence of colon cancer [20]. Moreover, hyperglicaemia may inhibit tumor response to therapies conferring resistance to chemotherapy-induced cell death [21][22][23][24]. Glucose metabolism has been shown to reduce p53-dependent transcription of apoptotic Puma gene, although the molecular mechanism of such inactivation was not elucidated [25].…”

Section: Introductionmentioning

confidence: 99%

High glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity

Garufi

D¿Orazi

2014

J Exp Clin Cancer Res

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Background: In response to diverse genotoxic stimuli p53 is activated as transcription factor to exert its tumor-suppressor function. P53 activation requires protein stabilization, nuclear localization and posttranslational modifications in key residues that may influence p53 selection of target genes. Among them, serine 46 (Ser46) phosphorylation is considered specific for apoptotic activation. Hyperglicaemia, the high blood glucose condition, may negatively affect tumor response to therapies through several mechanisms, conferring resistance to drug-induced cell death. However, whether high glucose might modify p53Ser46 phosphorylation has never been addressed. Methods and results: Here, we performed biochemical and molecular analyses in different cancer cell lines treated with chemotherapy in the presence or absence of high glucose condition. Analyses of p53 posttranslational modifications showed that drug-induced p53Ser46 phosphorylation was reduced by high glucose. Such reduction depended by high glucose-induced calyculin A-sensitive phosphatase(s), able to specifically target p53Ser46 phosphorylation. The specific effect on Ser46 phosphorylation was addressed by analysing Ser15 phosphorylation that instead was not modified by high glucose. In agreement, a constitutively phosphorylated Ser46D p53 mutant was resistant to high glucose. As a consequence of phosphoSer46 impairment, high glucose reduced the tumor cell response to drugs, correlating with reduced p53 apoptotic transactivation. The drug-induced apoptotic cell death, reduced by high glucose, was finally restored by the phosphatase inhibitor calyculin A. Conclusions: These data indicate that high glucose specifically inhibited Ser46 phosphorylation thus reducing p53 apoptotic activity. These results uncover a new mechanism of p53 inactivation providing an interesting novel molecular link between metabolic diseases such as diabetes or obesity and tumor progression and resistance to therapies.

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Section: Introductionmentioning

confidence: 99%

High glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity

Garufi

D¿Orazi

2014

J Exp Clin Cancer Res

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“…1, 2, 3, 4, 5, 6, 7 It appears that hyperglycemia may induce cancer cells to undergo a series of genetic and metabolic changes that allow them to develop a more malignant phenotype but also to become more resistant to conventional antineoplastic therapies including chemical agents. 8, 9, 10, 11, 12 Therefore, controlling hyperglycemia may have important therapeutic implications for cancer patients. However, the role of hyperglycemia in cancer therapy and the exact mechanisms remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…For HG treatment, low glucose culture medium was replaced with DMEM containing 4.5 g/l D -glucose (Life Technology-Invitrogen, Carlsbad, CA, USA) supplemented with 2% FBS for 24 h, as previously reported. 10, 12, 36 Chemotherapeutic drug ADR and ZnCl 2 were added in culture medium at 2 μ g/ml and 100 μ M, 36 respectively, for the indicated times. Glycolytic inhibitor 2-DG 34 (Santa Cruz Biotechnology, Dallas, TX, USA) was dissolved in DMSO and added to culture medium at 12 mM concentrations for 24 h. Irreversible, cell-permeable, pancaspase inhibitor zVAD-fmk 63 (Calbiochem, San Diego, CA, USA) was diluted in DMSO, stored at −20 °C and used at a final concentration of 40 μ M for 16 h.…”

Section: Methodsmentioning

confidence: 99%

“…2, 3, 4, 5, 6, 7 It appears that hyperglycemia may contribute to a more malignant cancer phenotype and that might inhibit tumor response to therapies, conferring resistance to chemotherapy-induced cell death. 8, 9, 10, 11, 12 A successful anticancer therapy is achieved when cancer cells undergo apoptosis. 13 Therefore, intrinsic or acquired deregulation in apoptotic cell death machinery becomes a determinant factor for cancer resistance to therapies.…”

mentioning

confidence: 99%

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ZnCl2 sustains the adriamycin-induced cell death inhibited by high glucose

Garufi

Trisciuoglio²,

Cirone

et al. 2016

Cell Death Dis

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Hyperglycemia, the condition of high blood glucose, is typical of diabetes and obesity and represents a significant clinical problem. The relationship between hyperglycemia and cancer risk has been established by several studies. Moreover, hyperglycemia has been shown to reduce cancer cell response to therapies, conferring resistance to drug-induced cell death. Therefore, counteracting the negative effects of hyperglycemia may positively improve the cancer cell death induced by chemotherapies. Recent studies showed that zinc supplementation may have beneficial effects on glycemic control. Here we aimed at evaluating whether ZnCl2 could counteract the high-glucose (HG) effects and consequently restore the drug-induced cancer cell death. At the molecular level we found that the HG-induced expression of genes known to be involved in chemoresistance (such as HIF-1α, GLUT1, and HK2 glycolytic genes, as well as NF-κB activity) was reduced by ZnCl2 treatment. In agreement, the adryamicin (ADR)-induced apoptotic cancer cell death was significantly impaired by HG and efficiently re-established by ZnCl2 cotreatment. Mechanistically, the ADR-induced c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) phosphorylation, inhibited by HG, was efficiently restored by ZnCl2. The JNK involvement in apoptotic cell death was assessed by the use of JNK dominant-negative expression vector that indeed impaired the ZnCl2 ability to restore drug-induced cell death in HG condition. Altogether, these findings indicate that ZnCl2 supplementation efficiently restored the drug-induced cancer cell death, inhibited by HG, by both sustaining JNK activation and counteracting the glycolytic pathway.

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“…Among patients with cancer, emerging experimental and clinical evidence suggests that hyperglycemia may affect health outcomes. Researchers have found that hyperglycemia may alter response to treatment (Biernacka et al, 2013;Ma et al, 2014;Trédan, Galmarini, Patel, & Tannock, 2007;Zeng et al, 2010) and result in other poor health outcomes (e.g., infection, mortality, longer HLOS) in patients with cancer (Storey & Von Ah, 2012). However, the significance of hyperglycemia for outcomes in patients with AML is largely unknown and has yet to be fully explored.…”

Section: Submittedmentioning

confidence: 99%