Curcumin induces pro-apoptotic endoplasmic reticulum stress in human leukemia HL-60 cells

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Abstract

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-2α, 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.

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Materials and methods

Materials. Curcumin (>95% pure) was isolated from the rhizomes of turmeric, as described earlier [16]. Tetrahydrocurcumin (>95% pure) was prepared from curcumin by hydrogenating the two double bonds conjugated to the β-diketone (see chemical structure shown in Fig. 1), as described previously [17]. The following reagents and antibodies were purchased from the indicated suppliers: RPMI-1640 medium and fetal bovine serum (FBS) from Gibco/Invitrogen (Carlsbad, CA); caspase-3, caspase-4, caspase-8,

Effects of curcumin and tetrahydrocurcumin (THC) on apoptosis of HL-60 cells

In human leukemia HL-60 cells, curcumin induced DNA fragmentation (Fig. 2A) and apoptotic cell death (Fig. 2B) in a dose-dependent manner. However, THC, a curcumin derivative that was chemically modified to lose an ability to form Michael adducts with intracellular proteins, did not induce apoptosis of HL-60 cells (Fig. 2). Induction of apoptosis by curcumin, but not by THC, was accompanied by decrease in anti-apoptotic Bcl-2 expression, increase in pro-apoptotic Bax expression, and release of

Discussion

Although the chemopreventive curcumin has been shown to induce apoptosis of a number of human cancer cell lines [13], [14], [15], the exact mechanism(s) accounting for curcumin-induced apoptosis is not yet fully defined. The present study provides important evidence to support the involvement of ER stress in induction of apoptosis by curcumin in HL-60 cells.

Curcumin (Fig. 1), which is a polyphenolic dienone that is potentially reactive as a Michael acceptor in reactions with nucleophiles such

Acknowledgment

This work was supported by Wonkwang University (2004).

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    These authors contributed equally to this work.

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