Downregulation of the Hexokinase II Gene Sensitizes Human Colon Cancer Cells to 5-Fluorouracil

Peng, Qiyu; Zhou, Jinming; Zhou, Qi; Pan, Feng; Zhong, Dongdong; Liang, Houjie

doi:10.1159/000153655

Cited by 24 publications

(20 citation statements)

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“…ATC has been characterized and classified as distinct from differentiated thyroid carcinoma by a higher percentage of HKII in the mitochondrial fraction (30). In particular, mitochondrion-bound HKII is correlated with high glycolytic rates in tumors, and inactivation of this enzyme can retard tumor growth by inhibiting glucose metabolism, which is enhanced in most tumor cells (31,32). We hypothesized that hNIS gene therapy with a safe dose of radioiodine could be used to treat cancer but might have limited cytotoxic effects.…”

Section: Discussionmentioning

confidence: 99%

Combined RNA Interference of Hexokinase II and ¹³¹I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma

et al. 2011

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The purpose of this study was to investigate the enhanced therapeutic effect of the combined use of shRNA (small hairpin RNA) therapy for the hexokinase II (HKII) gene and 131 I human sodium iodide symporter (hNIS) as a gene therapy for in vitro and in vivo treatment of anaplastic thyroid carcinoma cells (ARO) in an animal model. Methods: A recombinant lentivirus containing a plasmid with the hNIS gene driven by phosphoglycerate kinase promoter and green fluorescent protein (GFP) linked with an internal ribosome entry site sequence was produced. ARO cells were transfected with the virus and sorted by fluorescent activated cell sorting using GFP (ARO-NG). The messenger RNA expression of hNIS and GFP were evaluated with reverse-transcriptase polymerase chain reaction, and the function of hNIS was verified by 125 I uptake. The lentiviral vector expressing shRNA against HKII (Lenti-HKII shRNA) was constructed and used to infect ARO-NG cells. The effect of Lenti-HKII shRNA was evaluated by reverse-transcriptase polymerase chain reaction, 18 F-FDG uptake, and HK activity. An in vitro clonogenic assay was performed after Lenti-HKII shRNA therapy, 131 I therapy, and a combined therapy. The therapies were also applied in vivo to an animal model with an ARO-NG xenograft, and the effects were assessed with caliper measurements and 18 F-FDG PET. Results: ARO-NG cells showed an 125 I uptake 76-fold higher than the parent ARO cells. Compared with the uninfected ARO-NG cells, ARO-NG cells infected with Lenti-HKII shRNA had lower HKII messenger RNA expression, lower 18 F-FDG uptake, and HK activity. The proliferation of ARO-NG cells was inhibited by 131 I and Lenti-HKII shRNA therapies and further inhibited by the combined 131 I and Lenti-HKII shRNA therapy. Both the Lenti-HKII shRNA therapy and the 131 I therapy inhibited in vivo tumor growth in the tumor xenograft model. The combined Lenti-HKII shRNA and 131 I therapy resulted in a further decrease of tumor growth. Conclusion: Our results suggest that the combined HKII shRNA and 131 I therapy has a stronger antitumor effect than either the 131 I therapy or the HKII shRNA alone. Therefore, this combined therapy could be used as a powerful strategy for treating anaplastic thyroid carcinoma.

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Section: Discussionmentioning

confidence: 99%

Combined RNA Interference of Hexokinase II and ¹³¹I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma

et al. 2011

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“…Recent research has shown that specific inhibitors of key glycolytic enzymes may enhance the activity of anticancer drugs [45,46]. Furthermore, extensive trials have indicated that cancer cells with high glycolytic activity exhibit decreased sensitivity to anticancer agents [47].…”

Section: Discussionmentioning

confidence: 99%

Increased expression of enolase α in human breast cancer confers tamoxifen resistance in human breast cancer cells

Chang

Chen

et al. 2009

Breast Cancer Res Treat

113

102

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Enolase-alpha (ENO-1) is a key glycolytic enzyme that has been used as a diagnostic marker to identify human lung cancers. To investigate the role of ENO-1 in breast cancer diagnosis and therapy, the mRNA levels of ENO-1 in 244 tumor and normal paired tissue samples and 20 laser capture-microdissected cell clusters were examined by quantitative real-time PCR analysis. Increased ENO-1 mRNA expression was preferentially detected in estrogen receptor-positive (ER+) tumors (tumor/normal ratio >90-fold) when compared to ER-negative (tumor/normal ratio >20-fold) tumor tissues. The data presented here demonstrate that those patients whose tumors highly expressed ENO-1 had a poor prognosis with greater tumor size (>2 cm, *P = .017), poor nodal status (N > 3, *P = .018), and a shorter disease-free interval (<==1 year, *P < .009). We also found that higher-expressing ENO-1 tumors confer longer distance relapse (tumor/normal ratio = 82.8-92.4-fold) when compared to locoregional relapse (tumor/normal ratio = 43.4-fold) in postsurgical 4-hydroxy-tamoxifen (4-OHT)-treated ER+ patients (*P = .014). These data imply that changes in tumor ENO-1 levels are related to clinical 4-OHT therapeutic outcome. In vitro studies demonstrated that decreasing ENO-1 expression using small interfering RNA (siRNA) significantly augmented 4-OHT (100 nM)-induced cytotoxicity in tamoxifen-resistant (Tam-R) breast cancer cells. These results suggest that downregulation of ENO-1 could be utilized as a novel pharmacological approach for overcoming 4-OHT resistance in breast cancer therapy.

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“…34 Accordingly, ectopic expression of HK2 caused increased cell viability and resistance to the cytostatic drug cisplatinum in hepatocellular carcinoma cell lines, whereas knocking down HK2 in colon cancer cells increased sensitivity to 5-fluorouracil. 35,36 Similarly, HK1 attenuates the caspase-driven cell death in a range of human cell lines, including hematopoietic cells. 37 In line with our findings, it was shown that expression of HK3 protects HEK293 cells from oxidant-induced cell death.…”

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PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells

Federzoni

Valk

Torbett

et al. 2012

Blood

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The transcription factor PU.1 is a master regulator of myeloid differentiation and function. On the other hand, only scarce information is available on PU.1-regulated genes involved in cell survival. We now identified the glycolytic enzyme hexokinase 3 (HK3), a gene with cytoprotective functions, as transcriptional target of PU.1. Interestingly, HK3 expression is highly associated with the myeloid lineage and was significantly decreased in acute myeloid leukemia patients compared with normal granulocytes. Moreover, HK3 expression was significantly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples. In line with the observations in primary APL patient samples, we observed significantly higher HK3 expression during neutrophil differentiation of APL cell lines. Moreover, knocking down PU.1 impaired HK3 induction during neutrophil differentiation. In vivo binding of PU.1 and PML-RARA to the HK3 promoter was found, and PML-RARA attenuated PU.1 activation of the HK3 promoter. Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrophil differentiation and viability compared with control cells. Our findings strongly suggest that HK3 is: (1) directly activated by PU.1, IntroductionAcute promyelocytic leukemia (APL or AML-M3) accounts for 5% to 8% of acute myeloid leukemia (AML) subtypes. 1 APL is characterized by a balanced chromosomal translocation involving the promyelocytic leukemia (PML) gene on chromosome 15 and the retinoic acid receptor␣ (RARA) on chromosome 17 that results in expression of the oncogenic fusion gene PML-RARA. 2 PML-RARA is a gain-of-function protein that promotes leukemic transformation by impairing the formation of functional PML nuclear bodies 3 and repressing RARA target genes in a dominantnegative manner. 4 This repression interferes with gene expression programs involved in differentiation, apoptosis, and self-renewal and leads to increased cell survival and inhibition of terminal differentiation, with an accumulation of promyelocytes. The block in differentiation that is observed in APL cells can be reverted with pharmacologic doses of ATRA by triggering PML-RARA degradation and thus restoring normal myeloid differentiation (reviewed by de Thé and Chen 5 ).The Ets-family member PU.1 is a master transcriptional regulator of myeloid differentiation, 6,7 as evidenced in PU.1 null mice that die at birth because of the lack of functional myeloid cells. 7 Inhibition of PU.1-induced myeloid differentiation may represent a critical step in APL leukemogenesis. On the one hand, PU.1 is inhibited at the transcriptional level by PML-RARA binding to its promoter region 8 ; on the other hand, a recent study identified PML-RARA as a binding partner of PU.1, 4 resulting in repression of PU.1-activated genes. A majority of PU.1 target genes are directly involved in myeloid differentiation and function, such as CD11b, CD45, the granulocyte/macrophage colonystimulating factor receptor (GM-CSFR), myeloperoxidase, lysozyme, and neutrophil elastase (reviewed...

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Downregulation of the Hexokinase II Gene Sensitizes Human Colon Cancer Cells to 5-Fluorouracil

Cited by 24 publications

References 53 publications

Combined RNA Interference of Hexokinase II and ¹³¹I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma

Combined RNA Interference of Hexokinase II and ¹³¹I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma

Increased expression of enolase α in human breast cancer confers tamoxifen resistance in human breast cancer cells

PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells

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Downregulation of the Hexokinase II Gene Sensitizes Human Colon Cancer Cells to 5-Fluorouracil

Cited by 24 publications

References 53 publications

Combined RNA Interference of Hexokinase II and 131I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma

Combined RNA Interference of Hexokinase II and 131I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma

Increased expression of enolase α in human breast cancer confers tamoxifen resistance in human breast cancer cells

PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells

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Combined RNA Interference of Hexokinase II and ¹³¹I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma

Combined RNA Interference of Hexokinase II and ¹³¹I-Sodium Iodide Symporter Gene Therapy for Anaplastic Thyroid Carcinoma