Genistein sensitizes TRAIL-resistant human gastric adenocarcinoma AGS cells through activation of caspase-3.
The cytotoxic effect of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is limited in some cancer cells, including AGS gastric adenocarcinoma cells. However, treatment with TRAIL in combination with subtoxic concentrations of genistein sensitizes TRAIL-resistant AGS cells to TRAIL-mediated apoptosis. Combined treatment with genistein and TRAIL-induced chromatin condensation and sub-G1 phase DNA content. These indicators of apoptosis are correlated with the activation of death receptors (DR5) and induction of caspase-3 activity, which results in the cleavage of poly(ADP-ribose)polymerase. Both the cytotoxic effect and apoptotic characteristics induced by combined treatment were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role of caspase-3 in the observed cytotoxic effect. These results indicate that caspase-3 is a key regulator of apoptosis in response to combined genistein and TRAIL in human gastric adenocarcinoma AGS cells through the activation of DR5 and mitochondrial dysfunction.
Jin
Cheng-Yun
CY
Department of Biological Sciences, Pusan National University, Busan 609-735, Republic of Korea.
Park
Cheol
C
Cheong
JaeHun
J
Choi
Byung Tae
BT
Lee
Tae Ho
TH
Lee
Jae-Dong
JD
Lee
Won Ho
WH
Kim
Gi-Young
GY
Ryu
Chung Ho
CH
Choi
Yung Hyun
YH
D000230:Adenocarcinoma / Q000378:metabolism*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
D016588:Anticarcinogenic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D019833:Genistein; D053148:Caspase 3