Role of Bcl-xL in Doxorubicin-Induced Cell Death: Apoptosis and Mitotic Cell Death

Bcl-xL overexpressed in various human cancer cells contributes to resistance against various chemotherapeutic agents. In this study, we compared the role of Bcl-xL in high dose (HD) doxorubicin-induced apoptosis and low dose (LD) doxorubicin-induced mitotic cell death. In the first part of this study, we investigated whether anti-apoptotic effect of Bcl-xL on doxorubicin-induced apoptosis was associated with Bcl-xL-mediated modulation of signaling pathways. Bcl-xL overexpression in many cell types effectively blocked HD doxorubicin-induced apoptosis. HD Doxorubicin-induced activation of p38 or JNK was not affected by Bcl-xL overexpression. However, ERK2 was rapidly activated and its high activity was sustained in Bcl-xL-overexpressing cells treated with doxorubicin, whereas its activity was progressively decreased in doxorubicin-treated control cells. CREB, p90RSK, and NF-B, possible target molecules of ERK2, were also activated in Bcl-xL-overexpressing cells treated with doxorubicin. Enhanced expression of wild type ERK2 in control cells alleviated doxorubicin-induced apoptosis. Moreover, forced expression of dominant-negative ERK2 mutant in Bcl-xL overexpressing cells significantly increased the sensitivity to doxorubicin-induced apoptosis, suggesting the critical role of ERK2 in Bcl-xL-mediated blocking of doxorubicin-induced apoptosis. ERK2 activation was not observed in Bcl-2-overexpressing cells treated with doxorubicin, although Bcl-2 overexpression also could inhibit doxorubicin-induced apoptosis. These results suggest that doxorubicin-induced ERK2 activation is specifically mediated by Bcl-xL. Therefore, our results demonstrate that Bcl-xL-mediated ERK2 activation may provide one mechanism by which BcL-xL confers caner cells resistance to doxorubicin-induced apoptosis. In the second part of this study, we investigated whether Bcl-xL overexpression affected senescence and/or mitotic cell death induced by LD of doxorubicin. Bcl-xL overexpression effectively blocked apoptosis induced by high dose HD of doxorubicin, blocking the loss of mitochondrial membrane potential and activation of caspases in Huh-7 cells. In contrast, overexpression of Bcl-xL slightly delayed but not completely blocked doxorubicin-induced senescence-like phenotype (SLP) and the subsequent mitotic cell death. Loss of mitochondrial function and downregulation of mitosis-controlling proteins were also slightly delayed but not abolished by Bcl-xL overexpression. Clonogenicity of hepatoma cells exposed to LD doxorubicin was not enhanced by Bcl-xL overexpression. These results suggest that induction of senescence and/or mitotic cell death by LD doxorubicin may be more effective for Bcl-xL-overexpressing hepatoma cells, which are resistant to the apoptotic effect of chemotherapeutic agents.

Author dc:creator

• 김, 미애

Contributors dc:contributor

• 최, 경숙
• 대학원 의학과
• 200324250

Language dc:language

en

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000000213
000000000213

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/2290