Desipramine induces apoptosis in rat glioma cells via endoplasmic reticulum stress-dependent CHOP pathway.
Various antidepressants, mainly tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have exhibited potent anticancer properties in different cancer cell types. In the present study, desipramine (DMI), a representative of TCAs, was examined with respect to its apoptosis-inducing activity in rat C6 glioma cells and the underlying mechanism of action. DMI induced typical apoptotic morphology of chromatin condensation in rat glioma C6 cells and activated intracellular caspase 9 and caspase 3 with no change in mitochondrial membrane potential. Simultaneously, DMI significantly elevated expression of endoplasmic reticulum stress regulator CHOP/GADD153 and its targeting molecule GADD34. However, knockdown of CHOP by CHOP-specific short interfering RNA (siRNA) could decrease the activity of intracellular caspase 3 and the cytotoxicity of DMI to C6 cells. These results revealed that the CHOP-dependent endoplasmic reticulum (ER) stress pathway is responsible for DMI-induced apoptosis in C6 cells.
Ma
Jian
J
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Qiu
Yu
Y
Yang
Lan
L
Peng
Liang
L
Xia
Zheng
Z
Hou
Li-Na
LN
Fang
Chao
C
Qi
Hong
H
Chen
Hong-Zhuan
HZ
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003891:Desipramine / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005910:Glioma / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051742:Transcription Factor CHOP / Q000187:drug effects* / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; C497251:Ddit3 protein, rat; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; D003891:Desipramine