Silencing of <scp>GLUT</scp>‐1 inhibits sensitization of oral cancer cells to cisplatin during hypoxia

Shimanishi, Makoto; Ogi, Kazuhiro; Sogabe, Yohei; Kaneko, Takeshi; Dehari, Hironari; Miyazaki, Akira; Hiratsuka, Hiroyoshi

doi:10.1111/jop.12028

Cited by 41 publications

(40 citation statements)

References 27 publications

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“…In the present study, we examined the potential association between GLUT1 expression and cisplatin resistance and showed that HNSCC cells with high levels of GLUT1 mRNA and protein expression showed significantly higher resistance to cisplatin compared to the corresponding parental lines. Similar results were reported by Shimanishi et al, who used RNAi mediated knock-down of GLUT1 and showed that inhibition of GLUT1 expression rendered oral cancer cells more sensitive to cisplatin under hypoxic conditions [43]. Further investigation of the association between GLUT1 expression and sensitivity to chemotherapeutic agents is important for the design of combination treatments in oral cancer.…”

Section: Discussionsupporting

confidence: 73%

The Effects of GLUT1 on the Survival of Head and Neck Squamous Cell Carcinoma

Yang

Wang

et al. 2013

Cell Physiol Biochem

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Background/Aims: Cancer cells require increased nutrient uptake to support a high rate of proliferation, and the overexpression of glucose transporters, in particular GLUT1, is a common characteristic of human malignancies. Here, we investigated the relationship between the expression of GLUT1 and cell viability, colony forming ability and apoptosis of head and neck squamous cell carcinoma (HNSCC) in vitro and in a xenograft mouse model in vivo. Methods: Lentiviral mediated overexpression and knock-down of GLUT1 was performed in two oral cancer cell lines (CAL27 and SCC25). QRT-PCR and Western blot analysis were used to detect the mRNA and protein expression of GLUT1 and nuclear factor-kappa B (NFκB) p65 subunit. Cell viability and apoptosis were assessed by MTT and flow cytometry analyses, respectively. Colony formation assays were performed by staining with 0.5% crystal violet. The role of GLUT1 in HNSCC was examined in vivo through the generation of a CAL27 (or CAL27 with different transfections) nude mice xenograft model of HNSCC. Results: GLUT1 overexpression promoted cell viability and colony formation whereas GLUT1 silencing had the opposite effect. GLUT1 knock-down significantly increased the number of Annexin V positive cells in both cell lines and GLUT1 overexpression had the opposite effect, indicating that GLUT1 modulates apoptosis. Xenograft mouse models of GLUT1 knockdown and overexpression showed that GLUT1 expression was associated with poor survival and increased tumor growth. GLUT1 overexpression significantly upregulated the expression of NFκB-p65, and this effect was reversed by inhibition of GLUT1 expression. Conclusions: GLUT1 expression plays an important role in the survival of HNSCC, and its effects may be associated with the activation of the NFκB pathway.

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Section: Discussionsupporting

confidence: 73%

The Effects of GLUT1 on the Survival of Head and Neck Squamous Cell Carcinoma

Yang

Wang

et al. 2013

Cell Physiol Biochem

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“…In addition, another study described the fact that the uptake of various compounds, including nutrients such as glucose, was reduced in CDDP-resistant hepatoma cells compared with CDDP-sensitive cells (15). Moreover, a recent study reported that the knockdown of GLUT-1, which is a glucose transporter on the cell membrane, facilitated CDDP treatment, resulting in increased rates of apoptosis in oral cancer cells under hypoxic conditions (16), indicating that the glucose metabolism pathway is involved in CDDP resistance.…”

Section: Introductionmentioning

confidence: 99%

Synergistic cytotoxicity of cisplatin and Taxol in overcoming Taxol resistance through the inhibition of LDHA in oral squamous cell carcinoma

Lin

Lingling

Soloveiv³

et al. 2015

Oncology Letters

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The development of chemoresistance in patients represents a major challenge in cancer treatment. Lactate dehydrogenase-A (LDHA) is one of the principle isoforms of LDH that is expressed in breast tissue, controlling the conversion of pyruvate to lactate and also playing a significant role in the metabolism of glucose. The aim of this study was to identify whether LDHA was involved in oral cancer cell resistance to Taxol and whether the downregulation of LDHA, as a result of cisplatin treatment, may overcome Taxol resistance in human oral squamous cells. The OECM-1 oral epidermal carcinoma cell line was used, which has been widely used as a model of oral cancer in previous studies. The role of LDHA in Taxol and cisplatin resistance were investigated and the synergistic cytotoxicity of cisplatin and/or Taxol in oral squamous cells was analyzed. Cell viability was analyzed by MTT assay, LDHA expression was analyzed by western blot analysis and siRNA tranfection was performed to knock down LDHA expression. The present study results showed that decreased levels of LDHA were responsible for the resistance of oral cancer cells to cisplatin (CDDP). CDDP treatments downregulated LDHA expression, and lower levels of LDHA were detected in the CDDP-resistant oral cancer cells compared with the CDDP-sensitive cells. By contrast, the Taxol-resistant cancer cells showed elevated LDHA expression levels. In addition, small interfering RNA-knockdown of LDHA sensitized the cells to Taxol, but desensitized them to CDDP treatment, while exogenous expression of LDHA sensitized the cells to CDDP, but desensitized them to Taxol. The present study also revealed the synergistic cytotoxicity of CDDP and Taxol for killing oral cancer cells through the inhibition of LDHA. This study highlights LDHA as a novel therapeutic target for overcoming Taxol resistance in oral cancer patients using the combined treatments of Taxol and CDDP.

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“…This is because treatment of OSCC often fails due to local recurrence after surgical resection and lymph node metastasis; moreover, recurrent OSCC is resistant to chemotherapy. In addition to this, in vitro experimental data showed that human oral carcinoma cell lines HSC-2 and HSC-4 differed in their responses to cisplatin, chemotherapeutic agent, under hypoxia when cultured [3].…”

Section: Introductionmentioning

confidence: 87%

Suppression of NF-κB/p65 Inhibits the Proliferation in Oral Squamous Cancer Cells

Anbo¹,

Ogi²,

Sogabe³

et al. 2013

JCT

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Object: Hypoxia occurs when oxygen tension drops below normal limits, and malignant tumors often experience hypoxia, which activates the expression of genes through oxygen-sensitive transcription factors, including the hypoxiainducible factor (HIF) and the nuclear factor-κB (NF-κB). NF-κB pathway represents an attractive therapeutic target in both cancer cells and ischemic cells, which involves immune response. To investigate the expression of NF-κB target genes in oral squamous cancer carcinoma (OSCC) under hypoxia, we performed cDNA plate array analyses of 23 NF-κB-regulated genes in different cell lines. Our aim was to clarify the functions of NF-κB in OSCC under hypoxia. Results: We conducted an NF-κB reporter assay to examine NF-κB activation under hypoxia. This luciferase-based reporter assay showed that hypoxia induced NF-κB activation after 24 h of hypoxia. We also found that vascular endothelial growth factor-C (VEGF-C) of NF-κB-regulated genes was upregulated in both cell lines under hypoxia. We then tested the influence of NF-κB/p65 knockdown on these cells and NF-κB/p65 knockdown inhibited the proliferation of OSCC cells by colony assay. Conclusion: Based on these findings, we postulate that one mechanism by which hypoxic OSCC cells may involve NF-κB-mediated upregulation. Our results also indicate that the knockdown of NF-κB/p65 subunit lead to growth inhibition during hypoxia in OSCC cells. These results suggest that knockdown of NF-κB/p65 subunit could be a potential therapeutic option for patients with OSCC.

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Silencing of GLUT‐1 inhibits sensitization of oral cancer cells to cisplatin during hypoxia

Abstract: The results of this study suggest that knockdown of GLUT-1 inhibits sensitization of oral squamous cells to CDDP during hypoxia in HSC-2, Ca9-22, and SAS cells.

Cited by 41 publications

References 27 publications

The Effects of GLUT1 on the Survival of Head and Neck Squamous Cell Carcinoma

The Effects of GLUT1 on the Survival of Head and Neck Squamous Cell Carcinoma

Synergistic cytotoxicity of cisplatin and Taxol in overcoming Taxol resistance through the inhibition of LDHA in oral squamous cell carcinoma

Suppression of NF-κB/p65 Inhibits the Proliferation in Oral Squamous Cancer Cells

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