ACTIVATION OF PI3K/AKT PATHWAY BY DP103-P110α INTERACTION PROMOTES TUMORIGENIC CAPACITY OF GASTRIC CANCER CELLS

Abstract

Overall, in this study, a novel role of DP103 was identified in regulating the PI3K/Akt/mTOR pathway in gastric cancer, wherein, DP103 was initially found to be upregulated in gastric tumors versus normal gastric as well as adjacent normal gastric tissues. Further, DP103 knockdown studies showed downregulation of PI3K/Akt/mTOR pathway associated downstream functions such as proliferation,apoptosis, EMT as well as invasion and migration. This was associated with a decrease in the phosphorylation status of PI3K/Akt/mTOR pathway associated proteins with DP103 knockdown, indicative of potential role of DP103 in regulating this pathway in gastric cancer. Most importantly, DP103 was found to interact with p110α, the catalytic subunit of PI3K, by immunoprecipitation studies, undermining for the first time a novel role of DP103 in regulating PI3K/Akt/mTOR pathway in gastric cancer. Additionally, DP103-p110α interaction also played a crucial role in stabilization of p110-p85 heterodimer, the complete PI3K protein. Thus, our data suggested a novel function of DP103 in regulating the PI3K/Akt/mTOR pathway by interacting with p110α, catalytic subunit of PI3K. This DP103-p110α interaction aids in constitutive activation of the PI3K/Akt/mTOR pathway with an increase in PI3K kinase activity eventually resuting in increased proliferation, survival, invasion and migration. Thus, targeting DP103- p110α interaction could pave way towards a more targeted approach for gastric cancer treatment.