Activation of PKR/eIF2α signaling cascade is associated with dihydrotestosterone-induced cell cycle arrest and apoptosis in human liver cells.
Androgen receptor (AR) signaling plays an important role in the development and progression of several liver diseases, including hepatocellular carcinoma (HCC) and non-alcoholic fatty liver disease (NAFLD). Dihydrotestosterone (DHT) is the active metabolite of the major circulating androgen, testosterone. In this study, we investigated the effect of DHT on human liver cells. We found that DHT not only induces cell cycle arrest but also initiates apoptosis in androgen-sensitive liver cells, such as SMMC-7721 and L02. Importantly, DHT/AR induces the activation of RNA-dependent protein kinase (PKR)/eukaryotic initiation factor-2 alpha (eIF2α) cascades in androgen-sensitive liver cells. PKR/eIF2α activation-induced growth arrest and DNA damage-inducible gene 153 (GADD153) and heat shock protein 27 (Hsp27) expression contribute to cell cycle arrest in response to DHT. It is notable that DHT administration results in androgen-sensitive liver cells apoptosis, at least in part, through PKR/eIF2α/GADD153 cascades. These results suggest that the androgen/AR pathway plays a pivotal role in liver cell growth and apoptosis regulating, whose deregulation might be involved in the pathogenesis of liver diseases.
Department of Biochemistry of Luzhou Medical College, Luzhou, Sichuan, China. dryrun2502@163.com
Rongyang
R
Dai
Dongmei
D
Yan
Juan
J
Li
Shaokun
S
Chen
Youping
Y
Liu
Run
R
Chen
Chunyan
C
Duan
Mei
M
Wei
Hong
H
Li
Tao
T
He
D000726:Androgen Antagonists / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D013196:Dihydrotestosterone / Q000494:pharmacology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005485:Flutamide / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*
C410798:AR protein, human; D000726:Androgen Antagonists; C497249:DDIT3 protein, human; D015852:Eukaryotic Initiation Factor-2; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D051742:Transcription Factor CHOP; D005485:Flutamide; D019892:eIF-2 Kinase