Resistance to radiation-induced apoptosis in Bcl-2-expressing cells is reversed by depleting cellular thiols.
The mechanism by which Bcl-2 oncogene expression inhibits radiation-induced apoptosis has been investigated in two mouse lymphoma cell lines: line LY-as is radiation sensitive, displays substantial radiaton-induced apoptosis, and expresses low levels of Bcl-2; line LY-ar is radiation-resistant, displays a low apoptosis propensity, and expresses 30-fold higher amount of Bcl-2 protein than does the sensitive line. We observed that upon incubation in cystine/methionine-free (C/M-) medium, radiation-induced apoptosis in the LY-ar cells was restored to levels comparable to that seen in the LY-as cells. lntracellular glutathione (GSH) concentrations in LY-ar cells incubated in C/M- medium plummeted to 50% of control values within 2 h. LY-ar cells treated with diethyl maleate (DEM) or diamide, agents that deplete cellular thiols, had increased susceptibility to radiation-induced apoptosis in a manner similar to C/M- medium. These results are consistent with the general idea that Bcl-2 expression blocks apoptosis through an antioxidant pathway that involves cellular thiols. That Bcl-2-expressing tumor cells can be sensitized by exogeneous agents that modify cellular thiols offers strategies for overcoming such resistance.
Mirkovic
N
N
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Voehringer
D W
DW
Story
M D
MD
McConkey
D J
DJ
McDonnell
T J
TJ
Meyn
R E
RE
D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D053938:DNA Fragmentation; D004307:Dose-Response Relationship, Radiation; D019254:Genes, bcl-2; D005978:Glutathione / Q000378:metabolism; D007700:Kinetics; D008223:Lymphoma; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D011836:Radiation Tolerance; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019328:Buthionine Sulfoximine; D005978:Glutathione