Pdk1 inhibitor bx795 improves cisplatin and radio-efficacy in oral squamous cell carcinoma by downregulating the pdk1/cd47/akt-mediated glycolysis signaling pathway

Shin Pai, Vijesh Kumar Yadav, Kuang Tai Kuo, Narpati Wesa Pikatan, Chun Shu Lin, Ming Hsien Chien, Wei Hwa Lee, Michael Hsiao, Shao Chih Chiu, Chi Tai Yeh, Jo Ting Tsai

Research output: Contribution to journalArticlepeer-review

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 reprogramming 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: Im-munohistochemical 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 expres-sion. The combination of BX795 and cisplatin markedly reduced in OSCC cell’s epithelial-mesen-chymal 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 gly-colytic (LDHA/PFKP/PDK3) signaling and, enhanced or sensitizes OSCC to the anticancer drug effect through inducing apoptosis and DNA damage together with metabolic reprogramming. Con-clusions: Therefore, the results from our current study may serve as a basis for developing new therapeutic strategies against chemo/radioresistant OSCC.

Original languageEnglish
Article number11492
JournalInternational journal of molecular sciences
Volume22
Issue number21
DOIs
Publication statusPublished - Nov 1 2021

Keywords

  • Cancer stem cells
  • CD47
  • Chemo/radioresistance
  • Glycolysis
  • OSCC
  • PDK1

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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