Death receptor pathways mediate targeted and non-targeted effects of ionizing radiations in breast cancer cells.
Delayed cell death by mitotic catastrophe is a frequent mode of solid tumor cell death after gamma-irradiation, a widely used treatment of cancer. Whereas the mechanisms that underlie the early gamma-irradiation-induced cell death are well documented, those that drive the delayed cell death are largely unknown. Here we show that the Fas, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and tumor necrosis factor (TNF)-alpha death receptor pathways mediate the delayed cell death observed after gamma-irradiation of breast cancer cells. Early after irradiation, we observe the increased expression of Fas, TRAIL-R and TNF-R that first sensitizes cells to apoptosis. Later, the increased expression of FasL, TRAIL and TNF-alpha permit the apoptosis engagement linked to mitotic catastrophe. Treatments with TNF-alpha, TRAIL or anti-Fas antibody, early after radiation exposure, induce apoptosis, whereas the neutralization of the three death receptors pathways impairs the delayed cell death. We also show for the first time that irradiated breast cancer cells excrete soluble forms of the three ligands that can induce the death of sensitive bystander cells. Overall, these results define the molecular basis of the delayed cell death of irradiated cancer cells and identify the death receptors pathways as crucial actors in apoptosis induced by targeted as well as non-targeted effects of ionizing radiation.
Luce
Audrey
A
CEA, DSV, iRCM, SREIT, Laboratoire de Cancérologie Expérimentale, Fontenay-aux-Roses, France.
Courtin
Aurélie
A
Levalois
Céline
C
Altmeyer-Morel
Sandrine
S
Romeo
Paul-Henri
PH
Chevillard
Sylvie
S
Lebeau
Jérôme
J
D017209:Apoptosis / Q000528:radiation effects*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D024201:Bystander Effect; D016923:Cell Death / Q000528:radiation effects; D045744:Cell Line, Tumor / Q000528:radiation effects; D053222:Fas Ligand Protein / Q000502:physiology; D005260:Female; D005720:Gamma Rays; D006801:Humans; D053218:Receptors, Death Domain / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D053222:Fas Ligand Protein; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha