Curcumin induces apoptosis of multidrug-resistant human leukemia HL60 cells by complex pathways leading to ceramide accumulation

Shakor, Abo Bakr Abdel; Atia, Mona; Ismail, Ismail Ahmed; Alshehri, Ali; El-Refaey, Hesham; Kwiatkowska, Katarzyna; Sobota, Andrzej

doi:10.1016/j.bbalip.2014.09.006

Cited by 35 publications

(15 citation statements)

References 51 publications

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“…SMs can be hydrolyzed to regenerate Cers by acid or neutral SMases [37]. Hydrolysis of SM by either enzymes is known to be activated by TNFα, oxidants, UV radiation [37-41], vitamin D [42] and curcumin [43]. Since 13’-COOHs inhibited DEGS and consequently decreased de novo synthesis of Cers, the increase of Cers in the prolonged treatment was likely caused by SMase-mediated SM hydrolysis, which resulted in further decrease of SMs.…”

Section: Discussionmentioning

confidence: 99%

Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice

Jang

Park

Rostgaard-Hansen

et al. 2016

Free Radical Biology and Medicine

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Vitamin E forms are substantially metabolized to various carboxychromanols including 13'-carboxychromanols (13'-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13'-COOH and δTE-13'-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13'-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13'-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygnease (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anti-cancer effects by 13'-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13'-COOHs increased intracellular dihydrosphingosin and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13'-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13'-COOHinduced cell death. Further, 13'-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13'-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13'-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents.

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Section: Discussionmentioning

confidence: 99%

Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice

Jang

Park

Rostgaard-Hansen

et al. 2016

Free Radical Biology and Medicine

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“…Several drugs have been reported to acutely alter ceramide and/or Ca 2+ levels in the ER. For instance, curcumin stimulates de novo ceramide biosynthesis, presumably by directly activating ceramide synthases in the ER333435. Tamoxifen has been reported to increase ceramide levels by blocking glucosylceramide biosynthesis3637 whereas thapsigargin is known to release Ca 2+ from the ER lumen by inhibiting the sarco/endoplasmic reticulum Ca 2+ -ATPase, SERCA38.…”

Section: Resultsmentioning

confidence: 99%

“…As curcumin has been reported to trigger mitochondrial apoptosis333539, we first examined whether its ability to promote SMSr homo-oligomerization relies on activation of an apoptotic pathway. A time course experiment revealed that curcumin triggers SMSr oligomerization already within one hour (Fig.…”

Section: Resultsmentioning

confidence: 99%

ER residency of the ceramide phosphoethanolamine synthase SMSr relies on homotypic oligomerization mediated by its SAM domain

Cabukusta

Kol

Kneller

et al. 2017

Sci Rep

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SMSr/SAMD8 is an ER-resident ceramide phosphoethanolamine synthase with a critical role in controlling ER ceramides and suppressing ceramide-induced apoptosis in cultured cells. SMSr-mediated ceramide homeostasis relies on the enzyme’s catalytic activity as well as on its N-terminal sterile α-motif or SAM domain. Here we report that SMSr-SAM is structurally and functionally related to the SAM domain of diacylglycerol kinase DGKδ, a central regulator of lipid signaling at the plasma membrane. Native gel electrophoresis indicates that both SAM domains form homotypic oligomers. Chemical crosslinking studies show that SMSr self-associates into ER-resident trimers and hexamers that resemble the helical oligomers formed by DGKδ-SAM. Residues critical for DGKδ-SAM oligomerization are conserved in SMSr-SAM and their substitution causes a dissociation of SMSr oligomers as well as a partial redistribution of the enzyme to the Golgi. Conversely, treatment of cells with curcumin, a drug disrupting ceramide and Ca2+ homeostasis in the ER, stabilizes SMSr oligomers and promotes retention of the enzyme in the ER. Our data provide first demonstration of a multi-pass membrane protein that undergoes homotypic oligomerization via its SAM domain and indicate that SAM-mediated self-assembly of SMSr is required for efficient retention of the enzyme in the ER.

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“…Thus, it is critical to consider the difference of molecular species in active sphingolipids and the variation of time and localization in sphingolipid metabolism to understand the bona fide role of pathobiological sphingolipids in the cells. For example, curcumin-induced HL-60 apoptosis showed two phase-increases of ceramide accumulation by the activation of nSMase and subsequent inhibition of SMS, suggesting that each increase of ceramide plays a role in a different time course and localization in the process of cell death (Shakor et al, 2014). We have recently reported (1) the important role of SM in the microdomain of plasma membrane in transferrin-induced lymphoid cell proliferation and CXCL12-induced cell migration, (2) the positive role of ceramide in the nucleus in Fas-induced cell death even though the existence of sphingolipid metabolizing enzymes in the nucleus remains clarified and (3) the competitive role of ceramide and S1P in the cytosol in the regulation of mTOR in the process of autophagy (Taniguchi et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Recently in order to increase the cure rate of leukemia, there are many basic investigations to overcome the resistance to anti-cancer reagents by modulating the balance between pro-apoptotic and pro-survival sphingolipids. When acute promyelocytic leukemia-derived HL-60 cells and their multidrug-resistant counterpart (HL-60/VCR cells) were treated with curcumin, firstly nSMase2 was activated and then SMS was inhibited to make biphasic increase of ceramide generation, resulting in the overcome of the chemo-resistance in HL-60/VCR cells (Shakor et al, 2014). In addition, a second generation of BCR-ABL tyrosine kinase inhibitor nilotinib was shown to up-regulate CerS and down-regulate SK1 in chemo-resistant Meg-01 CML cells (Camgoz et al, 2011).…”

Section: Role Of Sphingolipids and Metabolizing Enzymes In Hematologimentioning

confidence: 99%

Role of Sphingolipids and Metabolizing Enzymes in Hematological Malignancies

Kitatani¹,

Taniguchi²,

Okazaki³

2015

Molecules and Cells

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Sphingolipids such as ceramide, sphingosine-1-phosphate and sphingomyelin have been emerging as bioactive lipids since ceramide was reported to play a role in human leukemia HL-60 cell differentiation and death. Recently, it is well-known that ceramide acts as an inducer of cell death, that sphingomyelin works as a regulator for microdomain function of the cell membrane, and that sphingosine-1-phosphate plays a role in cell survival/proliferation. The lipids are metabolized by the specific enzymes, and each metabolite could be again returned to the original form by the reverse action of the different enzyme or after a long journey of many metabolizing/synthesizing pathways. In addition, the metabolites may serve as reciprocal bio-modulators like the rheostat between ceramide and sphingosine-1-phosphate. Therefore, the change of lipid amount in the cells, the subcellular localization and the downstream signal in a specific subcellular organelle should be clarified to understand the pathobiological significance of sphingolipids when extracellular stimulation induces a diverse of cell functions such as cell death, proliferation and migration. In this review, we focus on how sphingolipids and their metabolizing enzymes cooperatively exert their function in proliferation, migration, autophagy and death of hematopoetic cells, and discuss the way developing a novel therapeutic device through the regulation of sphingolipids for effectively inhibiting cell proliferation and inducing cell death in hematological malignancies such as leukemia, malignant lymphoma and multiple myeloma.

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Curcumin induces apoptosis of multidrug-resistant human leukemia HL60 cells by complex pathways leading to ceramide accumulation

Cited by 35 publications

References 51 publications

Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice

Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice

ER residency of the ceramide phosphoethanolamine synthase SMSr relies on homotypic oligomerization mediated by its SAM domain

Role of Sphingolipids and Metabolizing Enzymes in Hematological Malignancies

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