EGF Protects Cells Against Dox-Induced Growth Arrest Through Activating Cyclin D1 Expression.
It has been reported that the antitumor drug doxorubicin (Dox) exerts its toxic effects via GATA-4 depletion and that over-expression of GATA-4 reverses Dox-induced toxicity and apoptosis; however, the precise mechanisms remain unclear. In this study, we observed, for the first time, that EGF protects cells against Dox-mediated growth arrest, G2/M-phase arrest, and apoptosis. Additionally, EGF expression was down-regulated in Dox-treated cells and up-regulated in GATA-4 over-expressing cells. Utilizing real-time PCR and western blotting analysis, we found that the expression of the cell cycle-associated protein cyclin D1 was inhibited in GATA-4-silenced cells and Dox-treated cells and was enhanced in GATA-4 over-expressing cells and EGF-treated cells. Furthermore, EGF treatment reversed the inhibited expression of cyclin D1 that was mediated by GATA-4 RNAi or Dox. Our results indicate that EGF, as a downstream target of Dox, may be involved in Dox-induced toxicity as well as in the protective role of GATA-4 against toxicity induced by Dox via regulating cyclin D1 expression, which elucidates a new molecular mechanism of Dox toxicity with important clinical implications.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou City, Henan, 450001, China.
Chun-Xia
CX
Yao
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou City, Henan, 450001, China.
Jia-Chen
JC
Shi
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou City, Henan, 450001, China.
Cai-Xia
CX
Ma
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou City, Henan, 450001, China.
Cheng-Juan
CJ
Xiong
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou City, Henan, 450001, China.
Yang-Liu
YL
Song
The People's Hospital of Henan Province, Zhengzhou University, Zhengzhou, Henan, 450001, China.
Shu-Feng
SF
Zhang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou City, Henan, 450001, China.
Shan-Feng
SF
Zhang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou City, Henan, 450001, China.
Ming-Xi
MX
Zang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
Li-Xiang
LX
Xue
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice
D000903:Antibiotics, Antineoplastic; C530104:CCND1 protein, human; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D004317:Doxorubicin
CELL GROWTH; CYCLIN D1; DOX; EGF; GATA-4