title: Antidepressant desipramine leads to C6 glioma cell autophagy: implication for the adjuvant therapy of cancer.
abstract: Depression is the most common psychiatric syndrome in cancer patients and adversely affects anti-cancer immune system and life quality of patients. Antidepressant desipramine (DMI) is clinically prescribed in the auxiliary treatment of cancer patients. Increasing evidences suggest that DMI has a broad spectrum of target-off biological effects, such as anticancer properties. Our previous study revealed that DMI at the clinical relevant concentrations could induce CHOP-dependent apoptotic death in C6 glioma cells. In this study, we further explored the pro-autophagic effect of DMI in C6 glioma cells and its underlying mechanism. Treatment with DMI could induce autophagic cell death characterized by the formation of autophagosome and the elevated level of autophagic protein Beclin-1 and cellular redistribution of marker LC3. Meanwhile, DMI inhibited the activation of PI3K-AKT-mTOR pathway which is considered as a negative regulator of autophagy. Furthermore, DMI activated PERK-eIF2α and ATF6 of endoplasmic reticulum (ER) stress pathway, while knockdown of PERK with the PERK-specific short interfering RNA (siRNA) could obviously attenuate the autophagy. The results strongly suggested that DMI could induce autophagy through the PERK-ER stress pathway in C6 glioma cells. Our findings provided new insights into another beneficial potential of antidepressant DMI in the adjuvant therapy of cancer.
authors.affiliation: Department of Pharmacology, Taishan Medical University School of Pharmaceutical Science, Changcheng Road, Taian 271016, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Hou
authors.forename: Zheng-Xing
authors.initials: ZX
authors.lastname: Rong
authors.forename: Peng
authors.initials: P
authors.lastname: Liang
authors.forename: Chao
authors.initials: C
authors.lastname: Fang
authors.forename: Hua-Fang
authors.initials: HF
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Qi
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D003891:Desipramine / Q000737:chemistry / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006863:Hydrogen-Ion Concentration; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D000928:Antidepressive Agents; D003891:Desipramine