Abstract:
Epidemiological studies and clinical evidences have proved a positive association
between diabetes and breast cancer. However, the possible biological links
between the two heterogeneous diseases have not been fully determined yet.
Recently, O-GlcNAcylation, a post translational modification of proteins has been
proposed to be associated with diabetes and breast cancer progression. O-GlcNAc
transferase (OGT) enzyme carries out O-GlcNAcylation by adding O-GlcNAc
group to proteins. The OGT plays a crucial role in regulating PI3K pathway
through activating/deactivating the Akt protein. In adipocytes, the overexpression
of OGT attenuates Akt signaling as a result the efficiency of insulin signaling is
reduced by impairing insulin responsive genes. However, increased expression of
OGT results in Akt activation in breast cancer cells, leading to enhanced cell
proliferation and inhibition of the apoptosis. Petri net modelling is an established
technique for modeling of such complex biological systems, which is employed
here to investigate the relationship and behaviors in diabetes and breast cancer
systems, the role of PI3K pathway and OGT in progression and crosstalk between
the two systems. We explored the overall behavior and dynamics of diabetes and
breast cancer systems during insulin resistance and hyperglycemia. We also
analyzed the effect of insulin resistance and hyperglycemia on OGT and cellular
processes in breast cancer. Moreover, we evaluated the anti-cancer effects by
OGT inhibition (shRNA and BZX) and anti-diabetic drug (Metformin), in breast
cancer. Our model predicted that the best alternative therapeutics to combat
breast cancer progression in diabetic patients could be a combination of OGT
inhibitor (BZX) and Metformin. This therapy not only moderates breast cancer
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cell proliferation, but also reduces the OGT expression which is a crucial target
for treating diabetes and breast cancer.
