Inhibition of apoptosis in acute promyelocytic leukemia cells leads to increases in levels of oxidized protein and LMP2 immunoproteasome.
On reaching maturity, animal organs cease to increase in size because of inhibition of cell replication activities. It follows that maintenance of optimal organ function depends on the elimination of oxidatively damaged cells and their replacement with new cells. To examine the effects of oxidative stress and apoptosis on the accumulation of oxidized proteins, we exposed acute promyelocytic leukemia cells to arsenic trioxide (As(2)O(3)) in the presence and absence of a general caspase inhibitor (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), which is known to inhibit caspase-induced apoptosis. We confirm that treatment of cells with As(2)O(3) induces apoptosis and leads to the accumulation of oxidized proteins. Furthermore, inhibition of caspase activities prevented As(2)O(3)-induced apoptosis and led to a substantial increase in accumulation of oxidized proteins. Moreover, inhibition of caspase activity in the absence of As(2)O(3) led to elevated levels of the LMP2 immunoproteasome protein. We also show that caspase inhibition leads to increases in the levels of oxidized proteins obtained by treatments with hydrogen peroxide plus ferrous iron. Collectively, these results suggest the possibility that an age-related loss in capacity to carry out apoptosis might contribute to the observed accumulation of oxidized proteins during aging and in age-related diseases.
Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-8012, USA.
Mohammed A S
MA
Khan
Hammou
H
Oubrahim
Earl R
ER
Stadtman
D000375:Aging / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010087:Oxides / Q000494:pharmacology; D011506:Proteins / Q000032:analysis / Q000378:metabolism*
D001152:Arsenicals; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D010087:Oxides; D011506:Proteins; C071313:LMP-2 protein; D006861:Hydrogen Peroxide; D007501:Iron; D003546:Cysteine Endopeptidases; D000077237:Arsenic Trioxide