PKM2 Modulation in Head and Neck Squamous Cell Carcinoma.

Verena Boschert,Jonas Teusch,Stefan Hartmann,Roman C Brands,Urs D A Müller-Richter

doi:10.3390/ijms23020775

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.

Highlights

Tumor cells rely on glycolysis for their growth, channeling high amounts of glucose through this pathway without subsequent oxidative phosphorylation (OxPhos) [1,2]
We looked at the protein levels of pyruvate kinase M2 (PKM2) expressed in the head and neck squamous cell carcinoma (HNSCC) cell lines using Western blot with an antibody recognizing PKM2 (Figure 1a,b on the left)
We repeated the experiment using an antibody specific for a PKM2 variant phosphorylated at Tyrosine 105 (P-PKM2 Tyr105)

Summary

Introduction

Tumor cells rely on glycolysis for their growth, channeling high amounts of glucose through this pathway without subsequent oxidative phosphorylation (OxPhos) [1,2]. The generated pyruvate is converted to lactate This phenomenon is called the Warburg effect, because it was first described by Otto Warburg in 1926 [3]. Why this aerobic glycolysis (normally cells employ this metabolic route only when oxygen is limited) is preferred by tumor cells is still a matter of debate [4]. Other explanations given for the preference of cancer cells for aerobic glycolysis are the modulation of reactive oxygen species or chromatin state. This switch in carbon metabolism could be favorable for the establishment of a microenvironment beneficial for tumor growth

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