ENO1 and Cancer

Abstract

α-Enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid during glycolysis. It is a multifunctional oncoprotein that is present both in cell surface and cytoplasm, contributing to hit seven out of ten "hallmarks of cancer." ENO1's glycolytic function deregulates cellular energetic, sustains tumor proliferation, and inhibits cancer cell apoptosis. Moreover, ENO1 evades growth suppressors and helps tumors to avoid immune destruction. Besides, ENO1 "moonlights" on the cell surface and acts as a plasminogen receptor, promoting cancer invasion and metastasis by inducing angiogenesis. Overexpression of ENO1 on a myriad of cancer types together with its localization on the tumor surface makes it a great prognostic and diagnostic cancer biomarker as well as an accessible oncotherapeutic target. This review summarizes the up-to-date knowledge about the relationship between ENO1 and cancer, examines ENO1's potential as a cancer biomarker, and discusses ENO1's role in novel onco-immunotherapeutic strategies.

Keywords: ENO1; cancer biomarker; glycolysis; hallmarks of cancer; oncotherapy; tumorigenesis.

Graphical abstract

Figure 1

Schematic representation of ENO1's multiple cellular functions, varied by its localization In the nucleus, MBP1 (c-MYC promoter binding protein), the alternative translation variant of ENO1, suppresses c-MYC and promotes the transcriptional level of ENO1 mRNA. The cytoplasm is the major expression site of ENO1, where ENO1 catalyzes glycolysis (exploited by cancer to promote tumor cell proliferation), maintains mitochondrial membrane stability, regulates signaling pathways, and reorganizes the cytoskeleton. When localized on the cell surface, ENO1 serves as a plasminogen receptor, which converts plasminogen into plasmin (exploited by cancer to promote metastasis, migration, and invasion). In addition, ENO1 can also partake components of exosomes.

Figure 2

Diagram of the assembly of ETP-PtFeNP (A) ETP-OXA-DHAC (tumor-targeting polymer) and PEG-OXA-DHAC (non-targeting polymer) form the polymeric shells. The oleic acid-Fe₃O₄ nanoparticles were synthesized in tetrahydrofuran with modification of oleic acid. Finally, ETP-PtFeNP was obtained via the competitive binding interaction between the terminal catechol group of polymers and the carboxyl group of oleic acid using the inversion dialysis method. (B) Schematic representation of enhanced anti-tumor immune responses with ETP-PtFeNP (ENO1-targeting peptide modified Pt prodrug-loaded Fe₃O₄ nanoparticles) treatment. ETP-PtFeNP reinforces immunogenic cell death (ICD) in cancer cells, leading to apoptosis. ETP-PtFeNP induces damage-associated molecular patterns (DAMPs), which increases the exposure of molecules such as calreticulin (CRT) and high-mobility group B1 (HMGB1). CRT act as an engulfment signal for dendritic cells (DCs) to target cancer cells, resulting in the cross-presentation of tumor antigens and anti-tumor-specific T cell responses. HMGB1 promotes the immunogenicity of CRT by interacting with receptors on DCs. The ETP-PtFeNP formulation targets PD-L2-mediated immunosuppression on the opposite side and restores the T cell cytotoxicity. Also, ETP-PtFeNP upregulates the secretion of IFN-γ in tumor tissues.

Figure 3

Schematic representation of the combinational effect of anti-ENO1 DNA vaccination and chemotherapy in pancreatic ductal adenocarcinoma mouse model The figure demonstrates that the vaccine induces various anti-tumor immune responses. Activated B cells and plasma cells produce anti-ENO1 antibodies. Membrane attack complex causes necrosis of tumor cells by inducing the complement-dependent cytotoxicity of tumor cells. Activated T cells release TNF-α and IFN-γ cytokines to damage tumor cells. Chemotherapy cyclophosphamide decreases the number of regulatory T cells (Tregs). There are two types of tumor-associated macrophage (TAM): M1-like phenotype TAM (M1-TAM), which releases anti-tumor interleukin-12 (IL-12) and M2-like phenotype (M2-TAM), which releases pro-tumor IL-10. Chemotherapy with GEM can upregulate TAM-M1 while downregulating TAM-M2.