Reconstitution of caspase-3 sensitizes MCF-7 breast cancer cells to radiation therapy.
Caspase-3 plays an important role in apoptotic execution. Caspase-3 deficiency or down-regulation has been reported in breast and other kinds of cancers. Given the redundancy of caspase cascade, however, the impact of caspase-3 deficiency/down-regulation on radiation-induced apoptosis remains to be defined. In this report, the specific role of caspase-3 in radiotherapy-induced apoptosis was studied using MCF-7 control (MCF-7/pv, caspase-3 deficient) and caspase-3 reconstituted MCF-7 (MCF-7/c3) breast cancer cells. Caspase-3 reconstitution significantly enhanced radiation-induced apoptosis, with a decrease in the survival fraction, an increase in caspase activation, cleavage of cellular death substrates and mitochondrial depolarization. We also found that the activation of caspase-7 was caspase-3-dependent in radiation-induced apoptosis, which suggests a mini-cascade among the effector caspases and that caspase-3 is essential for signal amplification. In comparing the patterns of death substrates cleavage in radiation-induced apoptosis with that in doxorubicin and TNF-alpha-induced apoptosis, we found that cleavage of lamin B and beta-actin was relatively more susceptible to radiation, which is enhanced in the presence of caspase-3, suggesting cytoskeleton proteins might be preferred markers for radiation-induced apoptosis. These data indicate that caspase-3 plays a critical role in radiotherapy-induced apoptosis, and suggest that caspase-3 deficiency may contribute to the radioresistance of breast cancers.
Yang
Xiao He
XH
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. xiaohe-yang@ouhsc.edu
Edgerton
Susan
S
Thor
Ann D
AD
D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000532:radiotherapy*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D004789:Enzyme Activation; D005246:Feedback; D005260:Female; D006801:Humans; D034921:Lamin Type B / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011836:Radiation Tolerance
D000199:Actins; D034921:Lamin Type B; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases