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

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.

Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance

“…Currently, the standard treatment for patients with OSCC is surgery for early-stage cancers, or surgery combined with chemotherapy, radiotherapy or targeted therapy for advanced cancer [3][4][5]. Although these constantly updated and advanced treatments have improved the quality of life of OSCC patients to a certain extent, the overall survival rate has not improved, and the 5-year survival rate of patients with advanced OSCC remains low (<50%) [6]. Radiotherapy is an important treatment strategy for patients with OSCC.…”

Roles of Mitochondria in Oral Squamous Cell Carcinoma Therapy: Friend or Foe?

“…In addition, some questions, beyond this review, also need to be answered. First, abundant studies have found OSCC with abnormal metabolism [ 191 , 192 ], however, the role of mitochondria in those processes is indistinct. Second, mitochondria can regulate the epigenetics of nuclear DNA [ 193 ], but how the nucleus regulates the epigenetics of mtDNA is indeterminate [ 194 ].…”

Beyond controlling cell size: functional analyses of S6K in tumorigenesis

“…Tan et al reported that BX795 and BX912 might function as PDK1 inhibitors to abolish PDK1-induced c-Myc expression, resulting in cell death and a reduction in tumor sphere formation [ 239 ]. Moreover, BX795 synergizes with cisplatin to markedly reduce the epithelial-mesenchymal transition (EMT) in oral squamous cell carcinoma [ 240 ]. Dichloroacetat synergizes with the nitric oxide synthase (NOS) inhibitor T1023, reducing tumor growth [ 241 ].…”