Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

by Selleckchem | Jun 10 2023

Background: Enolase 2 (ENO2) is a crucial glycolytic enzyme in cancer metabolic process and acts as a "moonlighting" protein to play various functions in diverse cellular processes unrelated to glycolysis. ENO2 is highly expressed in head and neck squamous cell carcinoma (HNSCC) tissues relative to normal tissues; however, its impact and underlying regulatory mechanisms in HNSCC malignancy remain unclear.

Methods: Molecular alterations were examined by bioinformatics, qRT-PCR, western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation, and ChIP-PCR assays. Metabolic changes were assessed by intracellular levels of ATP and glucose. Animal study was used to evaluate the therapeutic efficacy of the ENO inhibitor.

Results: ENO2 is required for HNSCC cell proliferation and glycolysis, which, surprisingly, is partially achieved by controlling PKM2 protein stability and its nuclear translocation. Mechanistically, loss of ENO2 expression promotes PKM2 protein degradation via the ubiquitin-proteasome pathway and prevents the switch of cytoplasmic PKM2 to the nucleus by inactivating AKT signaling, leading to a blockade in PKM2-mediated glycolytic flux and CCND1-associated cell cycle progression. In addition, treatment with the ENO inhibitor AP-III-a4 significantly induces HNSCC remission in a preclinical mouse model.

Conclusion: Our work elucidates the signaling basis underlying ENO2-dependent HNSCC development, providing evidence to establish a novel ENO2-targeted therapy for treating HNSCC.

Comments:

The study investigated the role of Enolase 2 (ENO2), a glycolytic enzyme, in head and neck squamous cell carcinoma (HNSCC). ENO2 was found to be highly expressed in HNSCC tissues compared to normal tissues, but its specific impact and regulatory mechanisms in HNSCC malignancy were not well understood.

Through various molecular and cellular assays, the researchers discovered that ENO2 is essential for HNSCC cell proliferation and glycolysis. Surprisingly, ENO2 achieves this by regulating the stability and nuclear translocation of another protein called PKM2. Loss of ENO2 expression led to the degradation of PKM2 via the ubiquitin-proteasome pathway and inhibited the translocation of PKM2 from the cytoplasm to the nucleus. This disruption resulted in a blockage of PKM2-mediated glycolytic flux and cell cycle progression associated with a protein called CCND1.

Furthermore, the study evaluated the therapeutic potential of an ENO inhibitor called AP-III-a4 using a preclinical mouse model of HNSCC. Treatment with the ENO inhibitor significantly induced remission of HNSCC in the animal model.

In conclusion, this research provides insights into the signaling mechanisms underlying ENO2-dependent HNSCC development. The findings suggest that targeting ENO2 could be a promising therapeutic approach for treating HNSCC.