Curcumin induces pro-apoptotic endoplasmic reticulum stress in human leukemia HL-60 cells.
Curcumin has been shown to induce apoptosis in many cancer cells. However, the molecular mechanism(s) responsible for curcumin-induced apoptosis is not well understood and most probably involves several pathways. In HL-60 cells, curcumin induced apoptosis and endoplasmic reticulum (ER) stress as evidenced by the survival molecules such as phosphorylated protein kinase-like ER-resident kinase, phosphorylated eukaryotic initiation factor-2alpha, glucose-regulated protein-78, and the apoptotic molecules such as caspase-4 and CAAT/enhancer binding protein homologous protein (CHOP). Inhibition of caspase-4 activity by z-LEVD-FMK, blockage of CHOP expression by small interfering RNA, and treatment with salubrinal, an ER inhibitor, significantly reduced curcumin-induced apoptosis. Removing two double bonds in curcumin, which was speculated to form Michael adducts with thiols in secretory proteins, resulted in a loss of the ability of curcumin to induce apoptosis as well as ER stress. Thus, the present study shows that curcumin-induced apoptosis is associated with its ability to cause ER stress.
Pae
Hyun-Ock
HO
Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan 570-749, Republic of Korea.
Jeong
Sun-Oh
SO
Jeong
Gil-Saeng
GS
Kim
Ki Mo
KM
Kim
Hak Sung
HS
Kim
Soon-Ai
SA
Kim
Youn-Chul
YC
Kang
Sung-Don
SD
Kim
Byeong-Nam
BN
Chung
Hun-Taeg
HT
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D053471:Caspases, Initiator / Q000378:metabolism; D003474:Curcumin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D034741:RNA, Small Interfering / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; C497249:DDIT3 protein, human; D034741:RNA, Small Interfering; C096277:tetrahydrocurcumin; D051742:Transcription Factor CHOP; C093516:CASP4 protein, human; D053471:Caspases, Initiator; D003474:Curcumin