Kaempferol mitigates Endoplasmic Reticulum Stress Induced Cell Death by targeting caspase 3/7

Abdullah, Ahmad; Ravanan, Palaniyandi

doi:10.1038/s41598-018-20499-7

Cited by 56 publications

(31 citation statements)

References 71 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…B). We have previously showed the bioactivity of KFL in ameliorating ER stress‐induced cell death with a reduction in the expression level of ER stress markers in IMR32 cells upon pretreatment with KFL . Our present study showed that KFL increased the expression of IRE1α without activating ER stress in IMR32 cells.…”

Section: Resultssupporting

confidence: 68%

“…Kaempferol (KFL) is a phytoestrogen that belongs to the class of flavonoids and is known to exhibit antioxidant, anti‐inflammatory, and anticancer activities . In our attempt toward identifying an inhibitor against ER stress‐induced cell death, we found KFL to rescue mammalian cells from apoptosis induced by multiple cell death inducers by acting as an allosteric inhibitor for executioner caspases . While performing the experiments we observed changes in morphology of IMR32 cells, a human neuroblastoma cell line with neurite like outgrowths, upon prolong incubation in the presence of KFL.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

et al. 2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…4B). We have previously showed the bioactivity of kaempferol in ameliorating ER stress induced cell death with a reduction in the level of ER stress markers expression in kaempferol pretreated conditions in IMR32 cells (Abdullah and Ravanan, 2018a). Our present study showed that kaempferol increases the expression of IRE1α without activating ER stress in IMR32 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Kaempferol is a phytoestrogen belongs to the class of flavonoids and known to exhibit antioxidant, anti-inflammatory and anti-cancer activity (Wang et al, 2018). In our attempt for identifying an inhibitor against ER stress induced cell death, we found kaempferol to rescue mammalian cells from apoptosis induced by multiple cell death inducers by acting as an allosteric inhibitor for executioner caspases (Abdullah and Ravanan, 2018a). While performing the experiments we observed the change in morphology of IMR32 cells, a human neuroblastoma cell line with neurite like outgrowths upon prolong incubation in the presence of kaempferol.…”

Section: Introductionmentioning

confidence: 99%

IRE1α is critical for kaempferol induced neuroblastoma differentiation

Abdullah

Talwar

Ravanan

2018

Preprint

Self Cite

View full text Add to dashboard Cite

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

“…The evidences demonstrated that kaempferol enhances lipophagy through induction of AMPK/mTOR signaling pathway, resulting in decreased ER stress and subsequently, a reduction in cell injury. Kaempferol can exert neuroprotective effect by regulation of ER stress (Abdullah & Ravanan, ). Again, kaempferol provides an inhibitory impact on GRP78 and CHOP expression to reduce ER stress.…”

Section: Kaempferol and Er Stressmentioning

confidence: 99%

Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress

Ashrafizadeh

Tavakol

Ahmadi

et al. 2019

Phytotherapy Research

View full text Add to dashboard Cite

Regulated cell death (RCD) guarantees to preserve organismal homeostasis. Apoptosis and autophagy are two major arms of RCD, while endoplasmic reticulum (ER) as a crucial organelle involved in proteostasis, promotes cells toward autophagy and apoptosis. Alteration in ER stress and autophagy machinery is responsible for a great number of diseases. Therefore, targeting those pathways appears to be beneficial in the treatment of relevant diseases. Meantime, among the traditional herb medicine, kaempferol as a flavonoid seems to be promising to modulate ER stress and autophagy and exhibits protective effects on malfunctioning cells. There are some reports indicating the capability of kaempferol in affecting autophagy and ER stress. In brief, kaempferol modulates autophagy in noncancerous cells to protect cells against malfunction, while it induces cell mortality derived from autophagy through the elevation of p-AMP-activated protein kinase, light chain-3-II, autophagy-related geness, and Beclin-1 in cancer cells. Noteworthy, kaempferol enhances cell survival through C/EBP homologous protein (CHOP) suppression and GRP78 increment in noncancerous cells, while it enhances cell mortality through the induction of unfolding protein response and CHOP increment in cancer cells. In this review, we discuss how kaempferol modulates autophagy and ER stress in noncancer and cancer cells to expand our knowledge of new pharmacological compounds for the treatment of associated diseases. K E Y W O R D S apoptosis, autophagy, cell death, endoplasmic reticulum stress, flavonoid, kaempferol

show abstract

Kaempferol mitigates Endoplasmic Reticulum Stress Induced Cell Death by targeting caspase 3/7

Cited by 56 publications

References 71 publications

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

IRE1α is critical for Kaempferol‐induced neuroblastoma differentiation

IRE1α is critical for kaempferol induced neuroblastoma differentiation

Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress

Contact Info

Product

Resources

About