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ATM regulates glioma migration and invasion primarily via MEK‐ERK and not AKT signaling (735.8)
Author(s) -
Allen Jasmine
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.735.8
Subject(s) - protein kinase b , cancer research , mapk/erk pathway , glioma , dna damage , cell migration , kinase , protein kinase a , biology , chemistry , signal transduction , microbiology and biotechnology , in vitro , dna , genetics
Glioblastoma multiforme (GBM) is a lethal brain cancer with a life expectancy of only 12‐15 months. Current standard treatment for GBM is surgery and chemoradiation. However, there are many difficulties when it comes to treating this aggressive brain cancer due to inherent radio‐ and chemo‐resistance. Hence, there is a critical need for new therapeutic approaches to make radiation/chemotherapy more effective. Ataxia telangiectasia (A‐T) patients are extremely sensitive to ionizing radiation. The protein mutated in A‐T, ATM (A‐T mutated), controls the cells’ response to radiation and is referred to as the DNA damage response (DDR). ATM is a master protein kinase that targets numerous proteins during the DDR including regulators of cell cycle checkpoints, DNA repair, and apoptosis. In addition, we have shown that without any radiation, ATM might regulate glioma dispersal. Using a highly specific inhibitor of the ATM kinase (ATMi), we recently showed that ATM regulates both ERK and AKT signaling and controls glioma cell migration and invasion in vitro. In order to determine whether MEK‐ERK and/or AKT signaling regulate migration and invasion downstream of ATM, glioma cells were exposed to a MEKi (PD0325901) or AKTi (MK‐2266) in ‘scratch’ and invasion assays. We found that MEKi inhibited both migration and invasion whereas ATKi did not affect migration and only partially (□40%) inhibited invasion. Then, we used a genetic approach and knocked‐down ATM in human glioma cells. In vitro growth and survival studies showed that ATM KD cells were more radiosensitive and grew slower than control cells. Furthermore, we recapitulated the findings with the ATMi, MEKi, and AKTi and showed that ATM KD cells have reduced ability to migrate and invade in vitro suggesting that ATM regulates glioma migration and invasion primarily via MEK‐ERK and less so via AKT signaling. Ongoing studies are determining whether orthotopic ATM KD tumors grow slower and are less invasive than matched control tumors. Grant Funding Source : Supported by NIH