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

Abstract

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.

ENO2 promotes anoikis resistance in anaplastic thyroid cancer by maintaining redox homeostasis

“…We hypothesized that the ENO2-mediated glycolysis process might play a crucial role in supplying energy for anoikis resistance in ATC cells. Previous studies have shown that ENO2 is significantly involved in the development of various tumors ( 22 , 28 , 53 ), prompting our assumption that regulating ENO2 expression might influence the fate of cells under detached culture conditions. Our in vitro experiments demonstrated that the knockdown of ENO2 significantly increased cell apoptosis in the SW1736 and 8305C cells, coupled with a significant decrease in sphere formation.…”

HSP90 inhibition suppresses tumor glycolytic flux to potentiate the therapeutic efficacy of radiotherapy for head and neck cancer

“…PKM2 is highly expressed in cancer cells and plays a critical role in promoting cell proliferation and survival. Recent studies have shown that PKM2 expression and activity are regulated by various signaling pathways, including oncogenic signaling pathways and metabolic stress pathways ( 29 , 30 ). In addition, PKM2 has been found to interact with other proteins involved in cell signaling and metabolism, such as HSP90 and hypoxia-inducible factor–1α, which can influence its activity and function ( 31 ).…”

“…The full-length Flag-tagged human HSP90AA1 was cloned into lentiviral pCDH-CMV-MCS-EF1-Puro (System Biosciences, Mountain View, CA) vector as previously described ( 7 ). The full-length HA-tagged human PKM gene was cloned into the pDONR-221 lentiviral expression vector (Invitrogen) as we previously described ( 29 ). pcDNA3.1-PFKP containing human PFKP gene was provided by Z. Lu ( 44 ).…”

Cellular senescence and metabolic reprogramming model based on bulk/single-cell RNA sequencing reveals PTGER4 as a therapeutic target for ccRCC

“…COL1A1 is the main constituent of type I collagen, and abnormal COL1A1 expression is associated with many cancers [ 39 – 41 ]. ENO2 (enolase 2) is a critical glycolytic enzyme in cancer metabolic processes [ 42 ]. Recent investigations have discovered that the overexpression of ENO2 encourages cell proliferation and glycolytic enrichment in papillary RCC [ 43 ].…”