Differential effects of resveratrol and novel resveratrol derivative, HS-1793, on endoplasmic reticulum stress-mediated apoptosis and Akt inactivation.
Since resveratrol (3,4',5 tri-hydroxystilbene), which has been shown to inhibit multistage carcinogenesis, is not a potent cytotoxic compound, several studies were undertaken to obtain synthetic analogues of resveratrol with potent activity. We previously reported that a resveratrol derivative HS-1793 exhibits stronger antitumor effects than resveratrol in several cancer cell types. The present study was undertaken to reveal precise mechanism by which HS-1793 induces cell death. The induction of CCAAT/enhancer-binding protein-homologous protein (CHOP) and glucose-regulated protein (GRP)-78, and ER stress-specific XBP1 splicing were found in HT29 human colon carcinoma cells treated with resveratrol. Conversely, these manifestations were not observed in HT29 cells treated with HS-1793. Inhibition of caspase-4 activity by z-LEVD-fmk significantly reduced the induction of apoptosis by resveratrol but not by HS-1793. These findings suggest that HS-1793, contrary to resveratrol, does not induce ER stress-mediated apoptosis. Importantly, we observed that HS-1793 but not resveratrol decreased phosphorylated Akt level. We also demonstrated that HS-1793, compared to resveratrol, exerted more effective apoptosis inducing activity in Akt-activated cells. Taken together, the stronger antitumor activity of HS-1793 originates, at least in part, from its ability for Akt inactivation.
Um
Hee Jung
HJ
Department of Immunology, School of Medicine, Keimyung University, Taegu 700-712, South Korea.
Bae
Jae Hoon
JH
Park
Jong-Wook
JW
Suh
Hongsuk
H
Jeong
Na Young
NY
Yoo
Young Hyun
YH
Kwon
Taeg Kyu
TK
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D061945:Caspase Inhibitors; D053471:Caspases, Initiator / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation; D019073:HT29 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009284:Naphthols / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D012118:Resorcinols / Q000494:pharmacology*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D000071717:X-Box Binding Protein 1
C523393:4-(6-hydroxy-2-naphthyl)-1,3-benzenediol; D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D009284:Naphthols; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D012118:Resorcinols; D013267:Stilbenes; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051742:Transcription Factor CHOP; D051057:Proto-Oncogene Proteins c-akt; C093516:CASP4 protein, human; D053471:Caspases, Initiator; D000077185:Resveratrol; D002118:Calcium