Abstract
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.
Highlights
Oral cancer is one of the most prevalent malignancies worldwide
The results revealed that radiation inhibited the clone counts in PDK1-depleted-SAS and TW2.6 Oral squamous cell carcinoma (OSCC) cells compared to that of the control (Figure 6C), suggesting that PDK1-deficient OSCC cells were sensitized toward radioresistance
The effect of PDK1 inhibition combined with 5 Gy irradiation effectively reduces the tumorsphere generating ability of OSCC-CSC’s cells (Figure 6G). These results showed that PDK1 inhibition sensitizes OSCC cells towards radiotherapy via reducing the expression of DNA repair enzymes, confirming that inhibition of the DNA repair process induces the radiosensitivity of OSCC cells
Summary
Oral cancer is one of the most prevalent malignancies worldwide. Oral cancerassociated mortality continues to rise, with a predicted global mortality rate of 67.1%; this makes it one of the major causes of cancer-related deaths [1]. Even with an aggressive chemotherapeutic approach, median survival rates of patients with OSCC remain low, with an estimated 5-year survival of less than 50% [3]. A better therapeutic approach is urgently required. Oral squamous cell carcinoma (OSCC) has a high prevalence and predicted global mortality rate of 67.1%, necessitating better therapeutic strategies. 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. Its aberrant expression in many malignancies is observed associated with glycolytic re-programming and chemo/radioresistance. Methods: to better understand the role of PDK1 in OSCC, we analyzed tissue samples from 62 patients with OSCC for PDK1 expression
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