Hexokinase 2 regulates G1/S checkpoint through CDK2 in cancer-associated fibroblasts

Hu, Junwei; Sun, Pengfei; Zhang, Daoxiang; Xiong, Wei; Mi, Jun

doi:10.1016/j.cellsig.2014.04.015

Cited by 51 publications

(36 citation statements)

References 31 publications

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“…All DEGs were classified into GO and KEGG categories to provide an overview of their biological functions and associated biochemical pathways. Many studies have shown the expression of individual hypoxia-related genes in different cells (28)(29)(30). In the present study, our analysis indicated that the upregulated genes were highly enriched in ECM organization (GO:0030198), protein binding (GO:0005515), extra ventricular cardiac muscle cell differentiation (GO:0055012), diphosphotransferase activity (GO:0016778) and the cytoplasm (GO:0005737).…”

Section: Discussionsupporting

confidence: 50%

Transcriptomic changes in human renal proximal tubular cells revealed under hypoxic conditions by RNA sequencing

Wang

et al. 2016

International Journal of Molecular Medicine

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Chronic hypoxia often occurs among patients with chronic kidney disease (CKD). Renal proximal tubular cells may be the primary target of a hypoxic insult. However, the underlying transcriptional mechanisms remain undefined. In this study, we revealed the global changes in gene expression in HK‑2 human renal proximal tubular cells under hypoxic and normoxic conditions. We analyzed the transcriptome of HK‑2 cells exposed to hypoxia for 24 h using RNA sequencing. A total of 279 differentially expressed genes was examined, as these genes could potentially explain the differences in HK‑2 cells between hypoxic and normoxic conditions. Moreover, 17 genes were validated by qPCR, and the results were highly concordant with the RNA seqencing results. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to better understand the functions of these differentially expressed genes. The upregulated genes appeared to be significantly enriched in the pathyway of extracellular matrix (ECM)-receptor interaction, and in paticular, the pathway of renal cell carcinoma was upregulated under hypoxic conditions. The downregulated genes were enriched in the signaling pathway related to antigen processing and presentation; however, the pathway of glutathione metabolism was downregulated. Our analysis revealed numerous novel transcripts and alternative splicing events. Simultaneously, we also identified a large number of single nucleotide polymorphisms, which will be a rich resource for future marker development. On the whole, our data indicate that transcriptome analysis provides valuable information for a more in depth understanding of the molecular mechanisms in CKD and renal cell carcinoma.

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Section: Discussionsupporting

confidence: 50%

Transcriptomic changes in human renal proximal tubular cells revealed under hypoxic conditions by RNA sequencing

Wang

et al. 2016

International Journal of Molecular Medicine

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“…CDK2 serves an important role in G 1 /S phase transition and S phase progression (8,9). In previous studies, it was also demonstrated that cyclin A-CDK2 activity was markedly upregulated in the early stages of apoptosis and that this upregulation was required for the progression of apoptosis induced by treatment with ginsenoside Rh2 (10).…”

Section: Introductionmentioning

confidence: 99%

Isoliquiritigenin induces apoptosis of human bladder cancer T24 cells via a cyclin-dependent kinase-independent mechanism

Yang

Yan

et al. 2017

Oncology Letters

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The aim of the present study was to investigate whether an increase in cyclin-dependent kinase 2 (CDK2) activity is involved in apoptosis of human bladder cancer T24 cells induced by isoliquiritigenin (ISL). The viability of T24 cells was estimated using a sulforhodamine B assay. Cell morphological changes were examined using Hoechst 33258 staining. The apoptotic rate was determined by staining cells with Annexin V-fluorescein isothiocyanate and propidium iodide labeling. The mitochondrial membrane potential (ΔΨm) was measured using 5,5,6,6-tetrachloro-1,1, 3,3-tetraethyl benzimidazole carbocyanine iodide. Alterations in the apoptosis-related regulators B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Bcl-2-interacting mediator of cell death (Bim), apoptotic protease-activating facter-1 (Apaf-1), caspase-9 and caspase-3 were determined using reverse transcription-polymerase chain reaction (PCR) and quantitative PCR methods. Western blot analysis was used to detect the expression of Bcl-2, Bax and caspase-3. CDK2 activity was measured using a spectrometric assay. Following treatment with ISL (between 30 and 70 µg/ml) for 24 h, typical apoptotic morphological changes were observed in T24 cells, exhibiting an edge set of chromosomes, nuclear condensation, nuclear fragmentation and other morphological features. Treatment with ISL increased the apoptotic ratio of T24 cells in a concentration-dependent manner and induced a decrease in the ΔΨm in a time-dependent manner. Treatment with ISL upregulated the expression of Bax, Bim, Apaf-1, caspase-9 and caspase-3, downregulated the expression of Bcl-2, and increased CDK2 activity. MK-8776 (an inhibitor of CDK2) antagonized the apoptosis induced by ISL, and, compared with treatment with ISL alone, pretreatment with MK-8776 inhibited the decrease in ΔΨm, downregulated the mRNA expression of Bax, Bim, Apaf-1, caspase-9 and caspase-3, and upregulated Bcl-2 mRNA expression. Western blot analysis demonstrated that, with increasing ISL concentration, the Bcl-2 expression level was significantly decreased (P<0.05), whereas caspase-3 and Bax expression levels were significantly increased (P<0.01). These results indicated that ISL treatment caused a significant decrease in the proliferation rate and increase in apoptosis of T24 cells. The mechanism by which ISL induces T24 cell apoptosis in vitro may be associated with an increase in CDK2 activity, downregulation of the ΔΨm and activation of caspase-3/caspase-9-mediated mitochondrial apoptotic signaling pathways.

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“…Knockdown of HK-II with siRNA reduces its mRNA and protein levels, as well as its activity, resulting in cell cycle arrest at the G1 phase, attenuated glycolysis, and apoptosis in cancer cells [31, 76–78]. Silencing of the HK-II gene sensitizes human colon cancer cells to 5-fluorouracil [79] and sensitizes parental lung cancer cells to cisplatin [80].…”

Section: Agents Targeted Inhibiting the Hk-ii-mediated Warburg Effectmentioning

confidence: 99%

Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma

Zhong

Zhou

2016

Oncotarget

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Radiotherapy is now widely used as a part of multidisciplinary treatment approaches for advanced laryngeal carcinoma and preservation of laryngeal function. However, the mechanism of the radioresistance is still unclear. Some studies have revealed that the Warburg effect promotes the radioresistance of various malignant tumors, including laryngeal carcinoma. Among the regulators involved in the Warburg effect, hexokinase-II (HK-II) is a crucial glycolytic enzyme that catalyzes the first essential step of glucose metabolism. HK-II is reportedly highly expressed in some human solid carcinomas by many studies. But for laryngeal carcinoma, there is only one. Till now, no studies have directly targeted inhibited HK-II and enhanced the radiosensitivity of laryngeal carcinoma. Accumulating evidence has shown that dysregulated signaling pathways often result in HK-II overexpression. Here, we summarize recent advances in understanding the association among the Warburg effect, HK-II, and the radioresistance of laryngeal carcinoma. We speculate on the feasibility of enhancing radiosensitivity by targeted inhibiting HK-II signaling pathways in laryngeal carcinoma, which may provide a novel anticancer therapy.

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Hexokinase 2 regulates G1/S checkpoint through CDK2 in cancer-associated fibroblasts

Cited by 51 publications

References 31 publications

Transcriptomic changes in human renal proximal tubular cells revealed under hypoxic conditions by RNA sequencing

Transcriptomic changes in human renal proximal tubular cells revealed under hypoxic conditions by RNA sequencing

Isoliquiritigenin induces apoptosis of human bladder cancer T24 cells via a cyclin-dependent kinase-independent mechanism

Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma

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