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Schofield et al. J Cancer Metastasis Treat 2020;6:10 I http://dx.doi.org/10.20517/2394-4722.2019.43 Page 3 of 12

Figure 1. The glycolysis pathway. Enolases catalyse the dehydration of 2-phospho-D-glycerate (2-P-glycerate) to phosphoenolpyruvate
(P-enolpyruvate) in the glycolysis pathway

shuttle between compartments, performing different functions when in different subcellular locations,
such as surface membrane plasminogen binding, controlling the overall metabolic state of the cell, stress-
related or acting as a heat-shock protein, RNA transport, mitochondrial membrane stability, and cell cycle
control [50-55] .

INCREASED ALPHA-ENOLASE EXPRESSION ENHANCES CELL PROLIFERATION IN A
VARIETY OF CANCERS
In most solid tumours, the Warburg effect causes an increase in total glycolysis under both hypoxic and
normoxic conditions [Figure 2]. Enhanced cell proliferation leads to increased anabolic needs, and cancer
cells remodel metabolic processes by diverting nutrients to anabolic pathways to satisfy increased cellular
[56]
energy demands . Therefore, the Warburg effect may provide cancer cells with an advantage when
competing with non-cancerous tissues for nutrients. This suggests that increased a-enolase expression will
contribute to enhanced proliferation commonly observed in cancer cells.

Indeed, upregulated a-enolase expression has been shown to regulate cell proliferation in various solid
tumours in vitro [11,13,57-61] , and to increase tumour growth in a HCT116 colorectal cancer xenograft
[11]
model in vivo [Table 2]. Conversely, silencing of a-enolase in glioma, pancreatic, lung, endometrial,
colorectal and breast cancer cells was found to induce cell cycle arrest and senescence, and also to reduce
tumour volume in CFPAC-1 pancreatic, MDA-MB-231 breast and U-87MG glioma xenograft models
in vivo [6,11,12,62,63] . Furthermore, a-enolase is also implicated in the control of apoptosis and sensitivity to
chemotherapeutic agents, as silencing of ENO1 in cancer cells induced apoptosis and increased sensitivity
to cisplatin and 5-fluorouracil in vitro [13,62,64] . Unexpectedly, cells respond to a-enolase silencing by inducing
catabolic adaptations that lead to restoration of pyruvate, acetyl-CoA bulk and oxidative phosphorylation,