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Page 2 of 12 Schofield et al. J Cancer Metastasis Treat 2020;6:10 I http://dx.doi.org/10.20517/2394-4722.2019.43

INTRODUCTION
[1]
All cancer cells have a high energy demand due to their increased rate of proliferation . Increased
[2]
glycolysis is considered a hallmark of cancer and investigating glycolytic enzymes may yield new
[3]
therapeutic approaches for cancer treatment. Enolases are key glycolytic enzymes , and increased
expression of one isoform, a-enolase, has been identified in several cancer types [4-22] . This review provides
an overview of the expression of a-enolase and key functions it controls in cancer cells, with a focus on the
potential role of a-enolase as a cancer prognostic biomarker or therapeutic target.

ENOLASE IS A GLYCOLYTIC ENZYME THAT HAS THREE ISOFORMS
Enolases (EC 4.2.1.11) are metalloenzymes that catalyse the dehydration of 2-phospho-D-glycerate
to phosphoenolpyruvate in the glycolysis pathway [Figure 1], and catalyse the hydration of
[3]
phosphoenolpyruvate to 2-phopho-D-glycerate in the reverse anabolic pathway during gluconeogenesis .
In mammals, the three genes ENO1, ENO2, ENO3 encode three isoforms, with expression being regulated
in a tissue-specific manner. Alpha-enolase (ENO1) is ubiquitously expressed, whereas g-enolase (ENO2)
[23]
is primarily expressed in neurons and neuroendocrine tissues, and b-enolase (ENO3) in muscle tissues .
[24]
Active enolase consists of a dimer in which two subunits face each other in an antiparallel formation ,
[25]
and requires two non-covalently bound magnesium ions as cofactors for enzyme activity .
ALPHA-ENOLASE IS A MULTI-FUNCTIONAL PROTEIN
Although many glycolytic enzymes are considered to be housekeeping proteins, a-enolase expression
can vary dramatically depending on the stress, metabolic, or pathological state of the cell. A retrospective
proteomic meta-analysis identified that a-enolase was the most differentially expressed protein in humans
[26]
and rodents irrespective of tissue type and pathological condition . Disrupted expression and/or activity
of a-enolase has been reported in several pathologies with distinct aetiologies, including Alzheimer’s
disease, systemic sclerosis, rheumatoid arthritis, bacterial infections and hepatic fibrosis [27-38] .

Apart from its role in the glycolytic pathway, recent studies have revealed that a-enolase is a multi-
functional protein that controls a variety of cellular processes, including proliferation, survival, migration
and invasion. Additionally, using an alternative transcription start codon, the ENO1 gene can produce a
37 kDa protein, c-myc promoter-binding protein (MBP-1). MBP-1 localises to the nucleus, where it acts
[39]
as a transcription repressor by binding to the c-myc P2 promoter , helping regulate and maintain the
function of the glycolysis pathway.

ALPHA-ENOLASE EXPRESSION IS ALTERED IN TUMOURS AND VARIES WITH CANCER
TYPE
The overexpression of a-enolase is associated with tumour development via a process known as aerobic
glycolysis or the Warburg effect. The Warburg effect has been hypothesised to be an adaptation mechanism
in cancer cells to support the biosynthetic requirements of rapid proliferation. Alpha-enolase expression
has been shown to be altered at the mRNA and/or protein level in a range of tumours [Table 1], and
generally upregulated in most, including acute myeloid leukaemia (AML), glioma, melanoma, lymphoma,
and colorectal, endometrial, gastric, head and neck, liver, ovarian and pancreatic cancer [4-22] .

ALPHA-ENOLASE CAN SHUTTLE BETWEEN CELLULAR COMPARTMENTS
Alpha-enolase can be localised to the cytoplasm and plasma membrane, as well as secreted in exosomes,
and its location varies with cancer type. For example, in pancreatic, breast and lung tumours, a-enolase
is localised to the plasma membrane [22,44,45] , whereas in melanoma, mesothelioma, non-small cell lung,
colorectal and prostate cancer a-enolase is also secreted and found in exosomes [43,46-49] . Alpha-enolase can