Myriocin induces apoptotic lung cancer cell death via activation of DR4 pathway

Choi, Kunhee; Jung, Young Suk; Kim, Dea Hwan; Song, Ju Kyung; Kim, Ji Young; Jung, Yu Yeon; Eum, So Young; Kim, Joo Hwan; Yoon, Na Young; Yoo, Hyun-jung; Han, Sang‐Bae; Hong, Jin Tae

doi:10.1007/s12272-013-0315-z

Cited by 15 publications

(11 citation statements)

References 47 publications

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“…1), indicating that sphingolipid synthesis is required for estrous cycle cell proliferation (Baranda-Avila et al 2013). However, further studies are need to establish whether changes in cell metabolism and membrane properties, as a consequence of shingolipd depletion by myriocin, can induce apoptotic cell death leading to inhibition of cellular growth, in a similar manner as was previously reported in lung cancer cells (Choi et al 2014). Moreover, the use of many sphingolipidderived reagents has been described, and they are useful tools to further explore the molecular mechanisms involved in sphingolipid synthesis and homeostasis (Chen et al 1999).…”

Section: Discussionmentioning

confidence: 68%

“…Our results are in line with these observations, suggesting an important role for sphingolipids in cell cycle progression. Since sphingolipids are important mediators of both cellular proliferation and programmed cell death (Gangoiti et al 2008, Choi et al 2014, Li et al 2017, it is important to investigate the precise role of individual sphingolipid species on uterine epithelial cell proliferation. Inhibitors downstream of SPT must be used in order to determine distinct roles of each species (Canals et al 2011) and further elucidate the diverse pathways affecting uterine epithelial cell proliferation.…”

Section: Figurementioning

confidence: 99%

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Sphingolipid synthesis and role in uterine epithelia proliferation

Cerbón¹,

Baranda-Ávila²,

Falcón-Muñoz³

et al. 2018

Reproduction

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Sphingolipids are involved in the regulation of cell proliferation. It has been reported that diacylglycerol and sphingosine-1-phosphate generation, during the synthesis of phospho-sphingolipids, is necessary for both, G1-S transition of cell cycle during the sustained activation of protein kinase C in various cell models (MDCK, and) and AKT pathway activation. During the estrous cycle of the rat, AKT signaling is the main pathway involved in the regulation of uterine cell proliferation. The aim of the present study was to investigate the role of sphingolipid synthesis during proliferation of uterine cells in the estrous cycle of the rat. On metestrus day, when both luminal and glandular uterine epithelia present the maximal BrdU-labeled cells (S phase cells), there was an increase in the relative abundance of total sphingomyelins, as compared to estrus day. Myriocin, a sphingolipid synthesis inhibitor administered on estrus day, before the new cell cycle of epithelial cells is initiated, decreased the abundance of sphingomyelin, accompanied by proliferation arrest in uterine epithelial cells on metestrus day. In order to study the sphingolipid signaling pathway affected by myriocin, we evaluated the activation of the PKC-AKT-GSK3b-Cyclin D3 pathway. We observed that total and phosphorylated protein kinase C diminished in uterine epithelial cells of myriocin treated animals. Interestingly, cyclin D3 nuclear localization was blocked by myriocin, concomitantly with a decrease in nuclear pRb expression. In conclusion, we demonstrate that sphingolipid synthesis and signaling are involved in uterine epithelial cell proliferation during the estrous cycle of the rat.

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Section: Discussionmentioning

confidence: 68%

Section: Figurementioning

confidence: 99%

Sphingolipid synthesis and role in uterine epithelia proliferation

Cerbón¹,

Baranda-Ávila²,

Falcón-Muñoz³

et al. 2018

Reproduction

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“…It was reported that numerous natural compounds showed anti-cancer effect via activation of DRs recently. In our previous study, we presented that BV suppressed cancer cell growth via activation of DR3 in NSCLC cells 10 , Myriocin induced apoptotic cell death through activation of DR4 in NSCLC cells 25 , (E)-2,4-bis (p-hydroxyphenyl)-2-butenal showed anti-cancer effect via activation of DR5 in NSCLC cells 12 . Our findings also showed that knock down of Fas or DR4 with siRNA partially abolished the inhibitory effect of PL on the NSCLC cell growth.…”

Section: Discussionmentioning

confidence: 93%

Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway

Zheng

Son

et al. 2016

Sci Rep

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Piperlongumine has anti-cancer activity in numerous cancer cell lines via various signaling pathways. But there has been no study regarding the mechanisms of PL on the lung cancer yet. Thus, we evaluated the anti-cancer effects and possible mechanisms of PL on non-small cell lung cancer (NSCLC) cells in vivo and in vitro. Our findings showed that PL induced apoptotic cell death and suppressed the DNA binding activity of NF-κB in a concentration dependent manner (0–15 μM) in NSCLC cells. Docking model and pull down assay showed that PL directly binds to the DNA binding site of nuclear factor-κB (NF-κB) p50 subunit, and surface plasmon resonance (SPR) analysis showed that PL binds to p50 concentration-dependently. Moreover, co-treatment of PL with NF-κB inhibitor phenylarsine oxide (0.1 μM) or p50 siRNA (100 nM) augmented PL-induced inhibitory effect on cell growth and activation of Fas and DR4. Notably, co-treatment of PL with p50 mutant plasmid (C62S) partially abolished PL-induced cell growth inhibition and decreased the enhanced expression of Fas and DR4. In xenograft mice model, PL (2.5–5 mg/kg) suppressed tumor growth of NSCLC dose-dependently. Therefore, these results indicated that PL could inhibit lung cancer cell growth via inhibition of NF-κB signaling pathway in vitro and in vivo.

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“…1 F. However, many necrotic cells with the triple addition of DL-PDMP plus D-NMAPPD plus myriocin were detected compared with the dual addition of DL-PDMP plus D-NMAPPD (data not shown). It was stipulated that the triple addition caused synergistical cell death by the combination of myriocin and anti-tumor drugs (DL-PDMP plus D-NMAPPD) against A549 cells as described previously [15] .…”

Section: Resultsmentioning

confidence: 99%

Palmitoyl-ceramide accumulation with necrotic cell death in A549 cells, followed by a steep increase in sphinganine content

Yamane

2015

Biochimie Open

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Ceramides (Cers) have recently been identified as key signaling molecules that mediate biological functions such as cell growth, differentiation, senescence, apoptosis, and autophagy. However, the functions of Cer accumulation in necrotic cell death remain unknown. The aim of this study was to clarify the relationship between Cer accumulation with inhibition of the conversion pathway of Cer and concomitant necrotic cell death. In order to minimize the effect of apoptosis against necrotic cell death, A549 cells having the inhibiting effect of caspase 9 by survivin were used in this study. Consequently, Cer accumulation in A549 cells would likely be associated with a pathway other than the mitochondrial caspase-dependent pathway of apoptosis. Here, we showed that the dual addition of a glucosyl-Cer synthase inhibitor and a ceramidase inhibitor to A549 cell culture induced palmitoyl-Cer accumulation with Cer synthase 5 expression and necrotic cell death with lysosomal rupture together with leakage of cathepsin B/alkalization after 2–3 h, although it is unknown in this study whether the necrotic cell death was caused by the lysosomal rupture. This Cer accumulation was followed by a steep increase in sphinganine base levels via the activation of serine palmitoyltransferase activity brought about by the increase in palmitoyl-coenzyme A concentration as a substrate after 5–6 h. The increase in palmitoyl-coenzyme A concentration was achieved by activation of the fatty acid synthetic pathway from acetyl coenzyme A.

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Myriocin induces apoptotic lung cancer cell death via activation of DR4 pathway

Cited by 15 publications

References 47 publications

Sphingolipid synthesis and role in uterine epithelia proliferation

Sphingolipid synthesis and role in uterine epithelia proliferation

Piperlongumine inhibits lung tumor growth via inhibition of nuclear factor kappa B signaling pathway

Palmitoyl-ceramide accumulation with necrotic cell death in A549 cells, followed by a steep increase in sphinganine content

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