Kaempferol Sensitizes Human Ovarian Cancer Cells-OVCAR-3 and SKOV-3 to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis via JNK/ERK-CHOP Pathway and Up-Regulation of Death Receptors 4 and 5

Zhao, Yang; Tian, Baohong; Wang, Yong; Ding, Haiying

doi:10.12659/msm.903552

Cited by 38 publications

(29 citation statements)

References 44 publications

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“…KFL treatment showed significant upregulation of apoptotic marker gene death receptor 5 ( DR5 ) and tumor necrosis factor receptor type 1 ( TNFR1 ). The upregulation of DR5 upon KFL treatment had been reported in other cancer cells as a contributing factor for KFL induced cell death in cancer cells . The significant upregulation of antiproliferative gene p21 observed in our study supports the cease in the proliferation of IMR32 cells after KFL treatment.…”

Section: Resultssupporting

confidence: 89%

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

et al. 2019

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Neuroblastoma is an embryonic malignancy that arises out of the neural crest cells of the sympathetic nervous system. It is the most common childhood tumor known for its spontaneous regression via the process of differentiation. The induction of differentiation using small molecules such as retinoic acid is one of the therapeutic strategies to treat the residual disease. In this study, we have reported the effect of kaempferol (KFL) in inducing differentiation of neuroblastoma cells in vitro. Treatment of neuroblastoma cells with KFL reduced the proliferation and enhanced apoptosis along with the induction of neuritogenesis. Analysis of the expression of neuron‐specific markers such as β‐III tubulin, neuron‐specific enolase, and N‐myc downregulated gene 1 revealed the process of differentiation accompanying KFL‐induced apoptosis. Further analysis to understand the molecular mechanism of action showed that the effect of KFL is mediated by the activation of the endoribonuclease activity of inositol‐requiring enzyme 1 alpha (IRE1α), an endoplasmic reticulum‐resident transmembrane protein. In silico docking analysis and biochemical assays using recombinant human IRE1α confirm the binding of KFL to the ATP‐binding site of IRE1α, which thereby activates IRE1α ribonuclease activity. Treatment of cells with the small molecule STF083010, which specifically targets and inhibits the endoribonuclease activity of IRE1α, showed reduced expression of neuron‐specific markers and curtailed neuritogenesis. The knockdown of IRE1α using plasmid‐based shRNA lentiviral particles also showed diminished changes in the morphology of the cells upon KFL treatment. Thus, our study suggests that KFL induces differentiation of neuroblastoma cells via the IRE1α ‐XBP1 pathway.

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Section: Resultssupporting

confidence: 89%

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

et al. 2019

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“…bladder, breast, cervical, colon, colorectal, endometrial, gastric, lung, and ovarian cancer (Nguyen et al, 2003;Li et al, 2009;Luo et al, 2011;Xie et al, 2013;Lee et al, 2014b;Kim et al, 2016;Yi et al, 2016;Kashafi et al, 2017;Zhao et al, 2017;Choi et al, 2018;Chuwa et al, 2018;Kim et al, 2018;Zhu et al, 2018;Zhang and Ma, 2019) sensitizing chemotherapy ABCC6, AKT1, BAX, BCL2/L1, BIRC5, CASP3/7/8/9/10, CDKN1A, FAS, JAK1, JNK, MAPK1/14, MYC, NFKB, PARP1, PIK3CA, ROS1, STAT3, TNFRSF10A, XIAP, ovarian, lung, and colorectal cancer (Luo et al, 2010;Kuo et al, 2015;Riahi-Chebbi et al, 2019) inhibiting metabolism SLC2A1/16A1 breast cancer (Azevedo et al, 2015) enhancing immunity CSF2, MAP2K1, MAPK2/3, PKC, PLC prostate cancer (Bandyopadhyay et al, 2008) Luteolin attenuating angiogenesis NOTCH1, VEGFA gastric cancer (Zang et al, 2017a) inhibiting metastasis AKT1, CDH1/2, CTNNB1, CYCD1, HES1, HEY1, MIR384, MMP2/3/7/9/16, NFKB, NFKBIA, NOTCH1, PIK3CA, PTN, SNAIL1/2, STAT3, VIM gastric, pancreatic, breast, lung, and colorectal cancer (Chen et al, 2013;Huang et al, 2015b;Zang et al, 2017b;Yao et al, 2019) promoting apoptosis AIF, AKT1, ANO1, AURKB, BANF1, BAX, BCL2/L1, BIRC5, CASP3/9, CCND1/E, CDKN1A, DEDD2, ENG, GAK, HSP90, HTERT, MAPK1/14/3, MCL1, MCL4, MIR107/139/155/21/ 224/301/340/34A/422A/5703/630, MTOR, MYC, NFE2L2, NFKBIA, NOTCH1, PIK3CA, PTPN6, SIRT1, STAT3, TET1, TP53, VRK1, breast, colon, gastric, lung, pancreatic, and prostate cancer (Kim et al, 2012b;Ma et al, 2015;Han et al, 2016;Song et al, 2017;Seo et al, 2017;Li et al, 2018;Jiang et al, 2018;Kang et al, 2019) sens...…”

Section: Discussionmentioning

confidence: 99%

Mapping Pharmacological Network of Multi-Targeting Litchi Ingredients in Cancer Therapeutics

Cao

Han

et al. 2020

Front. Pharmacol.

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Considerable pharmacological studies have demonstrated that the extracts and ingredients from different parts (seeds, peels, pulps, and flowers) of Litchi exhibited anticancer effects by affecting the proliferation, apoptosis, autophagy, metastasis, chemotherapy and radiotherapy sensitivity, stemness, metabolism, angiogenesis, and immunity via multiple targeting. However, there is no systematical analysis on the interaction network of "multiple ingredients-multiple targets-multiple pathways" anticancer effects of Litchi. In this study, we summarized the confirmed anticancer ingredients and molecular targets of Litchi based on published articles and applied network pharmacology approach to explore the complex mechanisms underlying these effects from a perspective of system biology. The top ingredients, top targets, and top pathways of each anticancer function were identified using network pharmacology approach. Further intersecting analyses showed that Epigallocatechin gallate (EGCG), Gallic acid, Kaempferol, Luteolin, and Betulinic acid were the top ingredients which might be the key ingredients exerting anticancer function of Litchi, while BAX, BCL2, CASP3, and AKT1 were the top targets which might be the main targets underling the anticancer mechanisms of these top ingredients. These results provided references for further understanding and exploration of Litchi as therapeutics in cancer as well as the application of "Component Formula" based on Litchi's effective ingredients.

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“…Flavonoids, being known for their anticancer activity, mimic estrogen in physiological systems, while some of them have been reported to induce neuritogenesis in neuroblastoma cells in vitro (Brown et al, 1998b; Sato et al, 1994b). Kaempferol had been reported before for its anticancer activity via multiple cellular pathways which includes triggering of ER stress, increasing the expression of DR5 receptor, via estrogen receptor expression and suppressing signal regulated kinases (Guo et al, 2017; Luo et al, 2012; Wang et al, 2013; Zhao et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

IRE1α is critical for kaempferol induced neuroblastoma differentiation

Abdullah

Talwar

Ravanan

2018

Preprint

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Neuroblastoma is an embryonic malignancy arises out of the neural crest cells of the sympathetic nervous system. It is the most common childhood tumor and well known for its spontaneous regression via the process of differentiation. The induction of differentiation using small molecule modulators such as all trans retinoic acid is one of the treatment strategies to treat the residual disease. In this study, we have reported the effect of kaempferol, a phytoestrogen in inducing differentiation of neuroblastoma cells in vitro. Treatment of neuroblastoma cells with kaempferol reduced the proliferation and enhanced apoptosis along with the induction of neuritogenesis. Analysis of the expression of neuron specific markers such as β III tubulin, neuron specific enolase and NRDG1 (N-myc down regulated gene 1) revealed the process of differentiation accompanying kaempferol induced apoptosis. Further analysis on understanding the molecular mechanism of action showed that the activity of kaempferol happened through the activation of the endoribonuclease activity of IRE1α (Inositol requiring enzyme 1 alpha), an endoplasmic reticulum (ER) resident transmembrane protein. The in silico docking analysis and biochemical assays using recombinant human IRE1α confirms the binding of kaempferol to the ATP binding site of IRE1α and thereby activating ribonuclease activity. Treatment of cells with the small molecule inhibitor STF083010 which specifically targets and inhibits the endoribonuclease activity of IRE1α showed reduced expression of neuron specific markers and curtailed neuritogenesis. The knock down of IRE1α using plasmid based shRNA lentiviral particles also showed diminished changes in the change in morphology of the cells upon kaempferol treatment. Thus our study suggests that kaempferol induces differentiation of neuroblastoma cells via the IRE1α-XBP1 pathway.

show abstract

Kaempferol Sensitizes Human Ovarian Cancer Cells-OVCAR-3 and SKOV-3 to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis via JNK/ERK-CHOP Pathway and Up-Regulation of Death Receptors 4 and 5

Cited by 38 publications

References 44 publications

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

Mapping Pharmacological Network of Multi-Targeting Litchi Ingredients in Cancer Therapeutics

IRE1α is critical for kaempferol induced neuroblastoma differentiation

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