The Multifarious Functions of Pyruvate Kinase M2 in Oral Cancer Cells

Abstract

Head and neck cancers, including oral squamous cell carcinoma (OSCC), are the sixth most common malignancies worldwide. OSCC frequently leads to oral dysfunction, which worsens a patient’s quality of life. Moreover, its prognosis remains poor. Unlike normal cells, tumor cells preferentially metabolize glucose by aerobic glycolysis. Pyruvate kinase (PK) catalyzes the final step in glycolysis, and the transition from PKM1 to PKM2 is observed in many cancer cells. However, little is known about PKM expression and function in OSCC. In this study, we investigated the expression of PKM in OSCC specimens and performed a functional analysis of human OSCC cells. We found that the PKM2/PKM1 ratio was higher in OSCC cells than in adjacent normal mucosal cells and in samples obtained from dysplasia patients. Furthermore, PKM2 expression was strongly correlated with OSCC tumor progression on immunohistochemistry. PKM2 expression was higher during cell growth, invasion, and apoptosis in HSC3 cells, which show a high energy flow and whose metabolism depends on aerobic glycolysis and oxidative phosphorylation. PKM2 expression was also associated with the production of reactive oxygen species (ROS) and integration of glutamine into lactate. Our results suggested that PKM2 has a variety of tumor progressive functions in OSCC cells.

Peroxidan Plays a Tumor-Promoting Role in Oral Squamous Cell Carcinoma

“…The results of this study are consistent with a previous report that PXDN is involved in the Warburg-like effect [ 6 ]. The Warburg effect on cancer cells is believed to promote cancer invasion and metastasis and is one of the 10 hallmarks of cancer [ 13 , 18 , 22 ]. However, the Warburg effect that occurs in the early stage of carcinogenesis has been reported to act as a tumor suppressor [ 23 ].…”

“…The conversion of PKM1 to PKM2 is found in many malignancies [ 16 ]. We previously reported that PKM2 is overexpressed in OSCC compared to normal oral mucosa as a result of a Warburg-like effect and is involved in tumor progression, hypoxia induction, cell growth, and invasion and is associated with the Ki-67 labeling index [ 18 ]. In addition, the Warburg effect increases PKM2 expression and promotes lactate production [ 17 ].…”

“…We previously observed that in OSCC, PKM2 overexpression is associated with cell growth, invasion, and the inhibition of apoptosis via the Warburg effect [ 18 ]. PKM2 activation status may be an indicator of tumor-promoting PXDN function.…”

Flavonoids against the Warburg phenotype—concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism

“…1). Conversely, in cancer cells, pyruvate is transformed into lactate by lactate dehydrogenase A (LDHA) and the yield of ATP is far lower, as only two ATP molecules are released per molecule of glucose through glycolysis [21,22]. Although glycolysis is less efficient than oxidative phosphorylation in generating ATP, it produces energy more rapidly per unit of glucose [23].…”

Downregulation of Jumonji-C domain-containing protein 5 inhibits proliferation by silibinin in the oral cancer PDTX model

“…In this metabolic flux, the pyruvate kinase muscle isozyme 2 (PKM2) might play an important role [ 6 ]. Previously studies revealed that overexpression of PKM2 associates with aggressive clinicopathological features and unfavorable prognosis in OSCC [ 7 , 8 ]. A study showed that Jumonji-C domain-containing protein 5 (JMJD5, KDM8) regulates nuclear translocation of PKM2 through direct physical binding and hinders the PKM2 tetrameric assembly and causes the nuclear translocation of PKM2 [ 9 ].…”