miR451 and AMPK Mutual Antagonism in Glioma Cell Migration and Proliferation: A Mathematical Model

Abstract

Glioblastoma multiforme (GBM) is the most common and the most aggressive type of brain cancer; the median survival time from the time of diagnosis is approximately one year. GBM is characterized by the hallmarks of rapid proliferation and aggressive invasion. miR-451 is known to play a key role in glioblastoma by modulating the balance of active proliferation and invasion in response to metabolic stress in the microenvironment. The present paper develops a mathematical model of GBM evolution which focuses on the relative balance of growth and invasion. In the present work we represent the miR-451/AMPK pathway by a simple model and show how the effects of glucose on cells need to be “refined” by taking into account the recent history of glucose variations. The simulations show how variations in glucose significantly affect the level of miR-451 and, in turn, cell migration. The model predicts that oscillations in the levels of glucose increase the growth of the primary tumor. The model also suggests that drugs which upregulate miR-451, or block other components of the CAB39/AMPK pathway, will slow down glioma cell migration. The model provides an explanation for the growth-invasion cycling patterns of glioma cells in response to high/low glucose uptake in microenvironment in vitro, and suggests new targets for drugs, associated with miR-451 upregulation.

MicroRNA-451 Exacerbates Lipotoxicity in Cardiac Myocytes and High-Fat Diet-Induced Cardiac Hypertrophy in Mice Through Suppression of the LKB1/AMPK Pathway

“…Indeed, it has been proposed that increased miR-451 levels increase cell proliferation. 40 In conclusion, miR-451 levels were markedly increased in palmitate-stimulated NRCMs and DIO mouse hearts. We found that Cab39 was a direct target of miR-451 in the heart.…”

MicroRNA-451 suppresses tumor cell growth by down-regulating IL6R gene expression

“…One article reported that CAB39 is a target gene of miR-451, and that it may regulate the CAB39/AMPK pathway [16]. Another group described that miR-451 downregulation allows the expression of the direct target gene macrophage migration inhibitory factor, which is involved in the expression of COX2.…”

The biology and mathematical modelling of glioma invasion: a review

“…In particular, a core control system of a single microRNA (miR-451) that regulates AMPK (the 5 0 -adenosine monophosphate activated protein kinase) signalling [45,164] linked to extracellular glucose was simulated. Recent experimental evidence suggests that, in a glucose-rich environment, miR-451 is up-regulated by tumour cells, leading to AMPK pathway inhibition and in turn cell proliferation.…”