Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines
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| Titel: | Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines |
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| Autoren: | Verhees, Femke, Demers, Imke, Legemaate, Dion, Jacobs, Robin, Hoeben, Ann, Kremer, Bernd, Speel, Ernst-Jan |
| Quelle: | Int J Oncol |
| Verlagsinformationen: | Spandidos Publications, 2025. |
| Publikationsjahr: | 2025 |
| Schlagwörter: | Head and Neck Neoplasms/drug therapy virology metabolism, cell survival, Cell Line, Cell Proliferation/drug effects, Papillomavirus Infections/drug therapy virology, Signal Transduction/drug effects, Phosphoinositide-3 Kinase Inhibitors/pharmacology, Thiazoles/pharmacology, Proto-Oncogene Proteins c-akt/metabolism, Humans, Piperazines/pharmacology, human papillomavirus, Pyridines/pharmacology, Tumor, Apoptosis/drug effects, apoptosis, Human Papillomavirus Viruses, cell line, Articles, Cyclin-Dependent Kinase 6/antagonists & inhibitors, TOR Serine-Threonine Kinases/metabolism antagonists & inhibitors, Aminopyridines/pharmacology, Protein Kinase Inhibitors/pharmacology therapeutic use, Squamous Cell Carcinoma of Head and Neck/drug therapy virology metabolism pathology, cell cycle, head and neck cancer, Cyclin-Dependent Kinase 4/antagonists & inhibitors metabolism, Phosphatidylinositol 3-Kinases/metabolism, Purines/pharmacology, Cell Survival/drug effects |
| Beschreibung: | Human papillomavirus (HPV)-positive and -negative head and neck squamous cell carcinoma (HNSCC) are often associated with activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway due to mutations or amplifications in PI3KCA, loss of PTEN or activation of receptor tyrosine kinases. In HPV-negative tumors, CDKN2A (encoding p16 protein) inactivation or CCND1 (encoding Cyclin D1 protein) amplification frequently results in sustained cyclin-dependent kinase (CDK) 4/6 activation. The present study aimed to investigate the efficacy of the CDK4/6 inhibitors (CDKi) palbociclib and ribociclib, and the PI3K/Akt/mTOR pathway inhibitors (PI3Ki) gedatolisib, buparlisib and alpelisib, in suppressing cell viability of HPV-positive and -negative HNSCC cell lines. Inhibitor efficacy was assessed in vitro using MTT assay and western blotting analysis. Cell cycle analysis was performed using flow cytometry and apoptosis was assessed using annexin V staining. Metabolic changes in terms of glycolysis and oxidative metabolism were measured by Seahorse XF96 extracellular Flux analysis. The results of the present study showed that both HPV-positive and -negative HNSCC cell lines were sensitive to PI3Ki. In general, PI3Ki decreased PI3K/Akt/mTOR pathway activity, resulting in apoptosis, and decreased oxidative and glycolytic metabolism. The CDKi were particularly effective in blocking HPV-negative cell line viability, showing decreased retinoblastoma expression and G1-phase cell cycle arrest, whereas apoptosis was not induced. Thus, PI3Ki and CDKi efficiently inhibited their respective pathways and HNSCC cell viability in vitro, with the latter occurring only in HPV-negative cell lines. Whereas PI3Ki induced apoptosis and attenuated cellular metabolism, CDKi led to cell cycle arrest. Further research should be performed to elucidate whether (a combination of) these inhibitors may be effective therapeutic agents for patients with HNSCC. |
| Publikationsart: | Article Other literature type |
| ISSN: | 1791-2423 1019-6439 |
| DOI: | 10.3892/ijo.2025.5719 |
| Rights: | CC BY NC ND |
| Dokumentencode: | edsair.doi.dedup.....b69abbd3c5a192cba57443fd4a3438a4 |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Human papillomavirus (HPV)-positive and -negative head and neck squamous cell carcinoma (HNSCC) are often associated with activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway due to mutations or amplifications in PI3KCA, loss of PTEN or activation of receptor tyrosine kinases. In HPV-negative tumors, CDKN2A (encoding p16 protein) inactivation or CCND1 (encoding Cyclin D1 protein) amplification frequently results in sustained cyclin-dependent kinase (CDK) 4/6 activation. The present study aimed to investigate the efficacy of the CDK4/6 inhibitors (CDKi) palbociclib and ribociclib, and the PI3K/Akt/mTOR pathway inhibitors (PI3Ki) gedatolisib, buparlisib and alpelisib, in suppressing cell viability of HPV-positive and -negative HNSCC cell lines. Inhibitor efficacy was assessed in vitro using MTT assay and western blotting analysis. Cell cycle analysis was performed using flow cytometry and apoptosis was assessed using annexin V staining. Metabolic changes in terms of glycolysis and oxidative metabolism were measured by Seahorse XF96 extracellular Flux analysis. The results of the present study showed that both HPV-positive and -negative HNSCC cell lines were sensitive to PI3Ki. In general, PI3Ki decreased PI3K/Akt/mTOR pathway activity, resulting in apoptosis, and decreased oxidative and glycolytic metabolism. The CDKi were particularly effective in blocking HPV-negative cell line viability, showing decreased retinoblastoma expression and G1-phase cell cycle arrest, whereas apoptosis was not induced. Thus, PI3Ki and CDKi efficiently inhibited their respective pathways and HNSCC cell viability in vitro, with the latter occurring only in HPV-negative cell lines. Whereas PI3Ki induced apoptosis and attenuated cellular metabolism, CDKi led to cell cycle arrest. Further research should be performed to elucidate whether (a combination of) these inhibitors may be effective therapeutic agents for patients with HNSCC. |
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| ISSN: | 17912423 10196439 |
| DOI: | 10.3892/ijo.2025.5719 |