Crosstalk between Bak/Bax and mTOR signaling regulates radiation-induced autophagy.
Bax and Bak, act as a gateway for caspase-mediated cell death. mTOR, an Akt downstream effector, plays a critical role in cell proliferation, growth and survival. The inhibition of mTOR induces autophagy, whereas apoptosis is a minor cell death mechanism in irradiated solid tumors. We explored possible alternative pathways for cell death induced by radiation in Bax/Bak-/- double knockout (DKO) MEF cells and wild-type cells, and we compared the cell survival: the Bax/Bak-/- cells were more radiosensitive than the wild-type cells. The irradiated cells displayed an increase in the pro-autophagic proteins ATG5-ATG12 and Beclin-1. These results are surprising in the fact that the inhibition of apoptosis resulted in increasing radiosensitivity; indicating that perhaps autophagy is the cornerstone in the cell radiation sensitivity regulation. Furthermore, irradiation upregulates autophagic programmed cell death in cells that are unable to undergo Bax/Bak-mediated apoptosis. We hypothesize the presence of a phosphatase-possibly PTEN, an Akt/mTOR negative regulator that can be inhibited by Bax/Bak. This fits with our hypothesis of Bax/Bak as a downregulator of autophagy. We are currently conducting experiments to explore the relationship between apoptosis and autophagy. Future directions in research include strategies targeting Bax/Bak in cancer xenografts and exploring novel radiosensitizers targeting autophagy pathways.
Moretti
Luigi
L
Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-5671, USA.
Attia
Albert
A
Kim
Kwang Woon
KW
Lu
Bo
B
D000818:Animals; D001343:Autophagy / Q000528:radiation effects*; D051379:Mice; D008954:Models, Biological; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000378:metabolism*
D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D011494:Protein Kinases; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases