CSC‐3436 inhibits TWIST‐induced epithelial–mesenchymal transition via the suppression of Twist/Bmi1/Akt pathway in head and neck squamous cell carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer deaths worldwide, especially in male. With poor prognosis, significant portions of patients with HNSCC die due to cancer recurrence and tumor metastasis after chemotherapy and targeted therapies. The HNSCC FaDu cell ectopic expression of Twist, a key transcriptional factor of epithelial–mesenchymal transition (EMT), which triggers EMT and results in the acquisition of a mesenchymal phenotype, was used as the cell model. Our results demonstrated that treatment with newly synthesized 2‐(3‐hydroxyphenyl)‐5‐methylnaphthyridin‐4‐one (CSC‐3436), a flavonoid derivative, elicited changes in its cell morphology, upregulated E‐cadherin messenger RNA and protein expression, downregulated N‐cadherin, vimentin, and CD133 (a marker associated with tumor‐initiating cells) in FaDu‐pCDH‐Twist cells. Moreover, CSC‐3436 exposure reduced B cell‐specific Moloney murine leukemia virus integration site 1 (Bmi1) expression regulated by Twist and further suppressed the direct co‐regulation of E‐cadherin by Twist and Bmi1. Interestingly, CSC‐3436 reduced EMT, cancer stemness, and migration/invasion abilities through the inhibition of the Twist/Bmi1‐Akt/β‐catenin pathway. Most importantly, our findings provided new evidence that CSC‐3436 played a crucial role in therapeutic targeting to Bmi1 and its molecular pathway in HNSCC, and it will be valuable in prognostic prediction and treatment.

Piperlongumine inhibits head and neck squamous cell carcinoma proliferation by docking to Akt

“…Our study suggested that Akt may be the target of PL through online pharmacologic analysis. Activated Akt promotes HNSCC proliferation and metastasis (Georgy et al, 2015), and drugs can inhibit HNSCC metastasis by attenuating Akt activation (Lai et al, 2019). Previous studies have shown that PL can inhibit Akt through PI3K/Akt pathway in a variety of tumors, such as triple negative breast cancer (TNBC) (Kumar & Agnihotri, 2019; Shrivastava et al, 2014).…”

Targeting cancer stem cells in squamous cell carcinoma

“…Down-regulation of BMI1 can reduce the cell sphere and colony formation 109 . Pharmacological targeting of BMI1, using a small molecule inhibitor, dramatically impaired tumorigenesis in HNSCC 75 , 110 , 111 …”

“…BMI1 can be directly regulated by TWIST, and synergistically promotes EMT and the tumor-initiating capability of HNSCC with TWIST 147 . In addition, overexpression of Twist results in upregulation of HNSCC CSC markers, such as ALDH and CD133 in HNSCC cell lines 111 …”

“…Inhibition of BMI1 by the small molecule inhibitor PTC-209, enhances the therapeutic effect of cisplatin and inhibits lymph node metastasis in HNSCC 75 . In addition, a study has shown that the flavonoid derivative 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436) can effectively inhibit EMT, cancer stemness, and migration/invasion abilities via downregulation of the Twist/Bmi1-Akt/β-catenin pathway 111 . Heat shock protein 90 inhibitors, KU711 and Ku757, are able to effectively target CSCs in HNSCC and inhibit the expression of BMI1 and EMT 163 …”

Clinical Significance of the Interleukin 24 mRNA Level in Head and Neck Squamous Cell Carcinoma and Its Subgroups: An In Silico Investigation

“…However, due to the lack of obvious early clinical symptoms, many HNSCC patients are diagnosed with advanced cancer. Moreover, the prognosis of HNSCC patients remains stagnant, with a considerable number of deaths due to recurrence and metastasis after chemotherapy and targeted therapy [ 8 ]. Furthermore, there are no suitable tumor markers for early diagnosis and prognosis evaluation of HNSCC [ 4 ].…”