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Autophagic cell death induced by TrkA receptor activation in human glioblastoma cells
Author(s) -
Hansen Katharina,
Wagner Bettina,
Hamel Wolfgang,
Schweizer Michaela,
Haag Friedrich,
Westphal Manfred,
Lamszus Katrin
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04753.x
Subject(s) - autophagy , low affinity nerve growth factor receptor , microbiology and biotechnology , programmed cell death , tropomyosin receptor kinase a , biology , neurotrophin , nerve growth factor , apoptosis , cancer research , receptor , biochemistry
The neurotrophin receptor tropomyosin‐related kinase A (TrkA) and its ligand nerve growth factor (NGF) are expressed in astrocytomas, and an inverse association of TrkA expression with malignancy grade was described. We hypothesized that TrkA expression might confer a growth disadvantage to glioblastoma cells. To analyze TrkA function and signaling, we transfected human TrkA cDNA into the human glioblastoma cell line G55. We obtained three stable clones, all of which responded with striking cytoplasmic vacuolation and subsequent cell death to NGF. Analyzing the mechanism of cell death, we could exclude apoptosis and cellular senescence. Instead, we identified several indications of autophagy: electron microscopy showed typical autophagic vacuoles; acridine orange staining revealed acidic vesicular organelles; acidification of acidic vesicular organelles was prevented using bafilomycin A1; cells displayed arrest in G2/M; increased processing of LC3 occurred; vacuolation was prevented by the autophagy inhibitor 3‐methyladenine; no caspase activation was detected. We further found that both activation of ERK and c‐ Jun N‐terminal kinase but not p38 were involved in autophagic vacuolation. To conclude, we identified autophagy as a novel mechanism of NGF‐induced cell death. Our findings suggest that TrkA activation in human glioblastomas might be beneficial therapeutically, especially as several of the currently used chemotherapeutics also induce autophagic cell death.