Role of OCT1 in regulation of miR-451-LKB1-AMPK-OCT1-mTOR core signaling network and cell invasion in glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with the short median survival time. GBM is characterized by the hallmarks of aggressive proliferation and critical cellular infiltration. miR-451 and their downstream molecules (LKB1, AMPK, OCT1, mTOR) are known to play a pivotal role in regulation of the balance of proliferation and aggressive invasion in response to metabolic stress in a tumor microenvironment (TME). Recent studies show that OCT1 and LKB1 play a significant role in regulation of the mutual inhibition between cell proliferation and migration. In this work, we develop a mathematical model of signaling pathway dynamics in GBM evolution with particular focus on the relative balance of proliferative capacity and invasion potential. In the present work we represent the miR-451/LKB1/AMPK/OCT1/mTOR pathway by a simple model and show how the effects of fluctuating glucose on tumor cells need to be reprogrammed by taking into account the recent history of glucose variations and an AMPK/miR-451 reciprocal feedback loop. The simulations show how variations in glucose significantly affect the level of signaling molecules and, in turn, lead to critical cell migration.