scholarly journals PDK1 Inhibitor BX795 Improves Cisplatin and Radio-Efficacy in Oral Squamous Cell Carcinoma by Downregulating the PDK1/CD47/Akt-Mediated Glycolysis Signaling Pathway

2021 ◽  
Vol 22 (21) ◽  
pp. 11492
Author(s):  
Shin Pai ◽  
Vijesh Kumar Yadav ◽  
Kuang-Tai Kuo ◽  
Narpati Wesa Pikatan ◽  
Chun-Shu Lin ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Strategies ◽  
Metabolic Reprogramming ◽  
Combination Group ◽  
Aberrant Expression ◽  
Mesenchymal Transition

Background: Oral squamous cell carcinoma (OSCC) has a high prevalence and predicted global mortality rate of 67.1%, necessitating better therapeutic strategies. Moreover, the recurrence and resistance of OSCC after chemo/radioresistance remains a major bottleneck for its effective treatment. Molecular targeting is one of the new therapeutic approaches to target cancer. Among a plethora of targetable signaling molecules, PDK1 is currently rising as a potential target for cancer therapy. Its aberrant expression in many malignancies is observed associated with glycolytic re-programming and chemo/radioresistance. Methods: Furthermore, to better understand the role of PDK1 in OSCC, we analyzed tissue samples from 62 patients with OSCC for PDK1 expression. Combining in silico and in vitro analysis approaches, we determined the important association between PDK1/CD47/LDHA expression in OSCC. Next, we analyzed the effect of PDK1 expression and its connection with OSCC orosphere generation and maintenance, as well as the effect of the combination of the PDK1 inhibitor BX795, cisplatin and radiotherapy in targeting it. Results: Immunohistochemical analysis revealed that higher PDK1 expression is associated with a poor prognosis in OSCC. The immunoprecipitation assay indicated PDK1/CD47 binding. PDK1 ligation significantly impaired OSCC orosphere formation and downregulated Sox2, Oct4, and CD133 expression. The combination of BX795 and cisplatin markedly reduced in OSCC cell’s epithelial-mesenchymal transition, implying its synergistic effect. p-PDK1, CD47, Akt, PFKP, PDK3 and LDHA protein expression were significantly reduced, with the strongest inhibition in the combination group. Chemo/radiotherapy together with abrogation of PDK1 inhibits the oncogenic (Akt/CD47) and glycolytic (LDHA/PFKP/PDK3) signaling and, enhanced or sensitizes OSCC to the anticancer drug effect through inducing apoptosis and DNA damage together with metabolic reprogramming. Conclusions: Therefore, the results from our current study may serve as a basis for developing new therapeutic strategies against chemo/radioresistant OSCC.

scholarly journals Aberrant Expression and Subcellular Localization of PER2 Promote the Progression of Oral Squamous Cell Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Fengyuan Guo ◽  
Qingming Tang ◽  
Guangjin Chen ◽  
Jiwei Sun ◽  
Junyi Zhu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Subcellular Localization ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Epithelial Mesenchymal Transition ◽  
Aberrant Expression ◽  
Mesenchymal Transition

Oral squamous cell carcinoma, one of the most prevalent cancer types in the world, has been confirmed under the influence of a key circadian gene, PER2, whose role has been identified in the development of some other types of cancers. However, the mechanism through which PER2 regulates the progress of OSCC remains largely unknown. In this study, we showed that besides the abnormal expression and subcellular localization of PER2 observed in OSCC tissues and cells as expected, these anomalous changes also existed in the adjacent noncancerous tissues, which was a novel finding in our research. The phase of PER2 rhythmic expression pattern in OSCC cells was later than that in oral keratinocytes in the protein level. In addition, we demonstrated that PER2 played as a resistant factor in the development of OSCC by upregulating TP53 and inhibiting epithelial-mesenchymal transition in vitro and in vivo. Taken together, our results identified that the development of OSCC is closely associated with PER2, the aberrant expression and subcellular localization of which facilitates the malignant progress.

scholarly journals CD47-SIRPα Signaling Induces Epithelial-Mesenchymal Transition and Cancer Stemness and Links to a Poor Prognosis in Patients with Oral Squamous Cell Carcinoma

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1658 ◽  
Author(s):  
Shin Pai ◽  
Oluwaseun Adebayo Bamodu ◽  
Yen-Kuang Lin ◽  
Chun-Shu Lin ◽  
Pei-Yi Chu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Transcription Factor ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Cellular Migration ◽  
Mesenchymal Transition

Background: Oral squamous cell carcinoma (OSCC), with high mortality rates, is one of the most diagnosed head and neck cancers. Epithelial-to-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs) are two keys for therapy-resistance, relapse, and distant metastasis. Accumulating evidence indicates that aberrantly expressed cluster of differentiation (CD)47 is associated with cell-death evasion and metastasis; however, the role of CD47 in the generation of CSCs in OSCC is not clear. Methods: We investigated the functional roles of CD47 in OSCC cell lines SAS, TW2.6, HSC-3, and FaDu using the bioinformatics approach, immunoblotting, immunofluorescence staining, and assays for cellular migration, invasion, colony, and orosphere formation, as well as radiosensitivity. Results: We demonstrated increased expression of CD47 in OSCC patients was associated with an estimated poorly survival disadvantage (p = 0.0391) and positively correlated with the expression of pluripotency factors. Silencing CD47 significantly suppressed cell viability and orosphere formation, accompanied by a downregulated expression of CD133, SRY-Box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and c-Myc. In addition, CD47-silenced OSCC cells showed reduced EMT, migration, and clonogenicity reflected by increased E-cadherin and decreased vimentin, Slug, Snail, and N-cadherin expression. Conclusion: Of therapeutic relevance, CD47 knockdown enhanced the anti-OSCC effect of radiotherapy. Collectively, we showed an increased CD47 expression promoted the generation of CSCs and malignant OSCC phenotypes. Silencing CD47, in combination with radiation, could provide an alternative and improved therapeutic efficacy for OSCC patients.

EPITHELIAL-MESENCHYMAL TRANSITION POTENTIAL ACTIVATED AFTER CHOLESTEROL DEPLETION IN ORAL SQUAMOUS CELL CARCINOMA

2020 ◽  
Vol 130 (3) ◽  
pp. e247
Author(s):  
Maria Gabrielly Barreto SAMPAIO ◽  
Rebeca Barros NASCIMENTO ◽  
Paloma Souza Gonçalves CERQUEIRA ◽  
Lucas Weber de Queiroz SILVA ◽  
Maria Fernanda Setúbal Destro RODRIGUES ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Epithelial Mesenchymal Transition ◽  
Cholesterol Depletion ◽  
Mesenchymal Transition ◽  
Transition Potential

scholarly journals Dysregulation of miR-200 family microRNAs and epithelial-mesenchymal transition markers in oral squamous cell carcinoma

2017 ◽  
Author(s):  
Ganesan Arunkumar ◽  
Arunagiri Deva Magendhra Rao ◽  
Mayakannan Manikandan ◽  
Harikrishnan Prasanna Srinivasa Rao ◽  
Shanmugam Subbiah ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition
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