Two distinctly altered cellular responses to DNA double-strand breaks in human neuroblastoma.
Neuroblastoma (NB), the most common extracranial solid tumors in children, presents with numerous genetic abnormalities that accumulate in a very short lifetime. To better understand this process, we have induced DNA double-strand breaks in NB cell lines and analyzed the activation of the ATM-H2AX/Chk2-p53 signaling pathway. We have found that NB cells could be classified into two distinct groups. The first group strongly expressed activated Chk2, displayed an important sub-G1 population, expressed very low levels of p21, and exhibited an attenuated G1 arrest. Conversely, the second group weakly expressed Chk2 pT68, displayed no sub-G1 cell population, strongly expressed p21, and exhibited a functional G1 arrest. These findings were independent of the MYCN amplification or p53 status of the NB cell lines tested. Interestingly, most p21 weakly expressing NB cells expressed neuron-specific enolase and Bcl2, two markers of N-type NB cells, but did not express vimentin, a marker of S-type NB cells. The expression profile was reversed in the p21 strongly expressing NB cells which highly expressed vimentin. Along with additional data, our findings lead us to propose that N-type-like NB cells would survive under stress conditions by antagonizing the Chk2-dependent apoptosis pathway, whereas S-type-like NB cells would survive by down-regulating Chk2 expression to facilitate the crossing of the senescence barrier.
Mergui
X
X
Université Paris Sud-11, CNRS, Institut Gustave Roussy, UMR812639, Villejuif, France.
Leteurtre
F
F
Lipinski
M
M
Bénard
J
J
Amor-Guéret
M
M
D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D053903:DNA Breaks, Double-Stranded; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014162:Transfection; D014746:Vimentin / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D019253:Proto-Oncogene Proteins c-bcl-2; D014746:Vimentin; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D020741:rho GTP-Binding Proteins