In:
Journal of Cellular Physiology, Wiley, Vol. 231, No. 1 ( 2016-01), p. 130-141
Kurzfassung:
The primary cause of treatment failures in acute myeloid leukemia is usually associated with defects in the apoptotic pathway. Several studies suggest that 2‐(4‐aminophenyl)‐7‐methoxybenzothiazole (7‐OMe‐APBT) may potentially induce apoptosis of cancer cells. Thus, the present study was conducted to explore the cytotoxic effect of 7‐OMe‐APBT on human leukemia U937 cells. The apoptosis of human leukemia U937 cells induced by 7‐OMe‐APBT was characterized by an increase in mitochondrial membrane depolarization, procaspase‐8 degradation, and tBid production. Down‐regulation of FADD blocked 7‐OMe‐APBT‐induced procaspase‐8 degradation and rescued the viability of 7‐OMe‐APBT‐treated cells, suggesting the involvement of a death receptor‐mediated pathway in 7‐OMe‐APBT‐induced cell death. Increased TNF‐α expression, TNFR2 expression, and p38 MAPK phosphorylation were noted in 7‐OMe‐APBT‐treated cells. Pretreatment with a p38 MAPK inhibitor abolished 7‐OMe‐APBT‐induced TNF‐α and TNFR2 up‐regulation. 7‐OMe‐APBT stimulated p38 MAPK/c‐Jun‐mediated transcriptional up‐regulation of TNFR2, while the increased TNF‐α mRNA stability led to TNF‐α up‐regulation in 7‐OMe‐APBT‐treated cells. Treatment with 7‐OMe‐APBT up‐regulated protein phosphatase 2A catalytic subunit α (PP2Acα) expression via the p38 MAPK/c‐Jun/ATF‐2 pathway, which, in turn, promoted tristetraprolin (TTP) degradation. Pretreatment with a protein phosphatase 2A inhibitor or TTP over‐expression abrogated TNF‐α up‐regulation in 7‐OMe‐APBT‐treated cells. Abolishment of TNF‐α up‐regulation or knock‐down of TNFR1/TNFR2 by siRNA restored the viability of 7‐OMe‐APBT‐treated cells. Taken together, our data indicate a connection between p38 MAPK‐mediated TNF‐α and TNFR2 up‐regulation and 7‐OMe‐APBT‐induced TNF‐α‐mediated death pathway activation in U937 cells. The same pathway also elucidates the mechanism underlying 7‐OMe‐APBT‐induced death of human leukemia HL‐60 cells. J. Cell. Physiol. 230: 130–141, 2016. © 2015 Wiley Periodicals, Inc.
Materialart:
Online-Ressource
ISSN:
0021-9541
,
1097-4652
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2016
ZDB Id:
1478143-8
SSG:
12
