Modeling and Analysis of PI3K/Akt Pathway in Diabetes and Breast cancer

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 11 cell proliferation, but also reduces the OGT expression which is a crucial target for treating diabetes and breast cancer.