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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
PKM2 Modulation in Head and Neck Squamous Cell Carcinoma
Verena Boschert1, Jonas Teusch1, Urs D A Müller-Richter1,2,3
1Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, D-97070 Würzburg, Germany.
Abstract:
The enzyme pyruvate kinase M2 (PKM2) plays a major role in the switch of tumor cells from oxidative phosphorylation to aerobic glycolysis, one of the hallmarks of cancer. Different allosteric inhibitors or activators and several posttranslational modifications regulate its activity. Head and neck squamous cell carcinoma (HNSCC) is a common disease with a high rate of recurrence. To find out more about PKM2 and its modulation in HNSCC, we examined a panel of HNSCC cells using real-time cell metabolic analysis and Western blotting with an emphasis on phosphorylation variant Tyr105 and two reagents known to impair PKM2 activity. Our results show that in HNSCC, PKM2 is commonly phosphorylated at Tyrosine 105. Its levels depended on tyrosine kinase activity, emphasizing the importance of growth factors such as EGF (epidermal growth factor) on HNSCC metabolism. Furthermore, its correlation with the expression of CD44 indicates a role in cancer stemness. Cells generally reacted with higher glycolysis to PKM2 activator DASA-58 and lower glycolysis to PKM2 inhibitor Compound 3k, but some were more susceptible to activation and others to inhibition. Our findings emphasize the need to further investigate the role of PKM2 in HNSCC, as it could aid understanding and treatment of the disease.
Insights
Pyruvate kinase M2 (PKM2) is often phosphorylated in head and neck squamous cell carcinoma (HNSCC), influencing cancer metabolism and stemness. Targeting PKM2 activity shows varied effects on glycolysis, suggesting personalized treatment potential.
Area of Science:
- Biochemistry
- Cancer Biology
- Metabolic Regulation
Background:
- Pyruvate kinase M2 (PKM2) is a key enzyme regulating the metabolic shift to aerobic glycolysis in cancer cells.
- Head and neck squamous cell carcinoma (HNSCC) is characterized by high recurrence rates, necessitating a deeper understanding of its metabolic drivers.
- PKM2 activity is modulated by allosteric regulators and posttranslational modifications, impacting cellular metabolism.
Purpose of the Study:
- To investigate the role and modulation of PKM2 in HNSCC.
- To examine PKM2 phosphorylation at Tyrosine 105 and its dependence on tyrosine kinase activity in HNSCC.
- To assess the impact of PKM2 activators and inhibitors on HNSCC cell glycolysis and correlate PKM2 expression with cancer stemness markers like CD44.
Main Methods:
- Real-time cell metabolic analysis to measure glycolysis.
- Western blotting to detect PKM2 phosphorylation at Tyr105 and expression levels.
- Treatment of HNSCC cells with PKM2 activator (DASA-58) and inhibitor (Compound 3k).
- Analysis of epidermal growth factor (EGF) signaling and CD44 expression.
Main Results:
- PKM2 is frequently phosphorylated at Tyrosine 105 in HNSCC cells, with levels dependent on tyrosine kinase activity and influenced by EGF.
- PKM2 phosphorylation correlates with CD44 expression, suggesting a role in cancer stemness.
- HNSCC cells exhibited increased glycolysis with PKM2 activation and decreased glycolysis with PKM2 inhibition, though responses varied among cell lines.
- Individualized responses to PKM2 modulation were observed, indicating differential susceptibility to activation or inhibition.
Conclusions:
- PKM2 phosphorylation at Tyr105 is a common event in HNSCC, linked to growth factor signaling and cancer stemness.
- Modulation of PKM2 activity impacts HNSCC cell glycolysis, but responses are heterogeneous.
- Further research into PKM2's role in HNSCC is crucial for developing targeted therapeutic strategies.
