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.

• Authors: 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
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 21 (Oct 25 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34768921 (Publication Type: Journal Article)

Chemical References

• BX795
• CD47 Antigen
• CD47 protein, human
• PDK1 protein, human
• Pyrimidines
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• RNA, Small Interfering
• Thiophenes
• Proto-Oncogene Proteins c-akt
• Cisplatin

Topics

• Adult
• Aged
• Apoptosis (drug effects)
• CD47 Antigen (metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• DNA Damage (drug effects)
• Disease Progression
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Glycolysis (drug effects)
• Humans
• Male
• Middle Aged
• Mouth Neoplasms (drug therapy)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrimidines (pharmacology)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase (antagonists & inhibitors, genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (genetics)
• Radiation Tolerance (physiology)
• Signal Transduction (drug effects)
• Squamous Cell Carcinoma of Head and Neck (drug therapy)
• Thiophenes (pharmacology)