Antiproliferative Activity of Crocin Involves Targeting of Microtubules in Breast Cancer Cells

Hire, Rupali; Srivastava, Shalini; Davis, Melissa B.; Konreddy, Ananda Kumar; Panda, Dulal

doi:10.1038/srep44984

Cited by 67 publications

(41 citation statements)

References 36 publications

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“…Other authors have described that crocin could inhibit endothelial cell apoptosis and protect the endothelium against damage [11, 26], which partially aligns with our studies. However, many studies demonstrated that crocin significantly suppressed cell proliferation in various cancer cells, including breast cancer cells and colorectal cancer cells [49-51]. These data contrast with our present results in endothelial cells and the discrepancy may be due to tissue differences in the effects of crocin.…”

Section: Discussioncontrasting

confidence: 57%

Crocin Improves the Endothelial Function Regulated by Kca3.1 Through ERK and Akt Signaling Pathways

Yang

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Based on the protective effect of crocin against cardiovascular diseases, we hypothesize that crocin could improve endothelial function through activating the eNOS(endothelial nitric oxide synthase) /NO pathway and/or the intermediate-conductance Ca²⁺-activated K⁺ channels (KCa3.1). Methods: In this study, rat aortic rings were used to assess the regulatory effect of crocin on vascular tone and nitric oxide, prostacyclin, and KCa3.1, all endothelial vasodilators, were analyzed for effects by crocin. The expression profiles of p-eNOS, total-eNOS, p-ERK, total-ERK, p-Akt, total-Akt, KCa3.1, CD31, thrombomodulin, ICAM-1 and VCAM-1 were tested by western blotting. KCa3.1 was also analyzed by qPCR and immunofluorescence staining. Fluorescence and confocal microscopy were used to determine NO generation and intracellular Ca²⁺. Both EdU and MTT assays were used to evaluate cell viability. Cellular migration was assessed using transwell assay. Results: Crocin relaxed pre-contracted artery rings through either NO or KCa3.1, but not PGI, in an endothelium-dependent manner. Furthermore, crocin increased p-eNOS, total-eNOS expression and NO production as well as intracellular Ca²⁺ in both HUVECs and HUAECs (Human Umbilical Artery Endothelial cells). Crocin also stimulated the expression of CD31, thrombomodulin and vascular cell adhesion molecule 1 (VCAM-1), as well as increased cellular proliferation and migration in vitro. Interestingly, we determined for the first time that by blocking or silencing KCa3.1 there was inhibition of crocin induced upregulation of p-eNOS and total-eNOS. Correspondingly, the KCa3.1 inhibitor TRAM-34 also reduced the expression of CD31, thrombomodulin and VCAM-1, as well as diminished intracellular Ca²⁺, cellular proliferation and migration. Finally, crocin stimulated the expression of p-ERK, total-ERK, p-Akt and total-Akt, however suppression of MEK and Akt inhibited this expression profile in endothelial cells. Conclusion: In the present study, these data strongly support the hypothesis that crocin could improve endothelial function through stimulation of the eNOS/NO pathway and other endothelial markers. This functional improvement is regulated by KCa3.1 via the MEK/ERK and PI3K/Akt signaling pathway.

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Section: Discussioncontrasting

confidence: 57%

Crocin Improves the Endothelial Function Regulated by Kca3.1 Through ERK and Akt Signaling Pathways

Yang

Liu

et al. 2018

Cell Physiol Biochem

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“…N = 5, each value represents mean ± SD, *p < 0.05 versus the NC mimic group. GAPDH: glyceraldehyde 3-phosphate dehydrogenase; HIF-1α: hypoxia-inducible factor-1α; KLF5: Krüppel-like factor 5; miR: microRNA; mut: mutant; NC: negative control; mRNA: messenger RNA; PCR: polymerase chain reaction; SD: standard deviation; wt: wild-type Evidence has accumulated that crocin has anticancer activities in many cancers (Festuccia et al, 2014;Hire et al, 2017;Mollaei et al, 2017). Its effect in gastric cancer is not fully understood, although a previous study found that it could trigger apoptosis of gastric adenocarcinoma AGS cells by increasing the Bax/Bcl-2 ratio (Hoshyar et al, 2013).…”

Section: Crocin Modulates Klf5 Expression By Elevating Mir-320 Exprmentioning

confidence: 99%

Crocin inhibits the migration, invasion, and epithelial‐mesenchymal transition of gastric cancer cells via miR‐320/KLF5/HIF‐1α signaling

Zhou

Shang

et al. 2019

Journal Cellular Physiology

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The biological activities of crocin, one of the main bioactive compounds of saffron, include anti‐inflammatory, antioxidant, antidepressant, and anticancer effects. Crocin has been shown to trigger the apoptosis of gastric cancer cells, but its effect on the metastasis of gastric cancer cells remains unclear. Krüppel‐like factor 5 (KLF5) and hypoxia‐inducible factor‐1α (HIF‐1α) are important transcription factors in the development of gastric cancer. KLF5 and HIF‐1α expression were analyzed in gastric cancer tissues and cells. Following exposure to crocin, AGS and HGC‐27 gastric cancer cells were assessed with regard to migration, invasion, and epithelial‐mesenchymal transition (EMT) as well as the expression of KLF5, HIF‐1α, and microRNA‐320 (miR‐320). The miR‐320/KLF5/HIF‐1α signaling pathway became the focus for further investigation of the mechanism of crocin in gastric cancer cell migration, invasion, and EMT. KLF5 and HIF‐1α expression were elevated in gastric cancer tissues and cells, and KLF5 expression was positively correlated with the HIF‐1α level in gastric cancer tissues. Crocin was associated with reduced expression of KLF5 and HIF‐1α, whereas miR‐320 expression was increased. Crocin also inhibited the migration, invasion, and EMT of gastric cancer cells. Upregulation of KLF5 attenuated crocin's function and elevated HIF‐1α expression. Dual‐luciferase reporter assay demonstrated that KLF5 was a target gene of miR‐320. Crocin modulated KLF5 expression via elevation of miR‐320 expression. In conclusion, crocin inhibits the EMT, migration, and invasion of gastric cancer cells, and this activity is mediated through miR‐320/KLF5/HIF‐1α signaling.

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“…Three major components of saffron are crocin, picrocrocin, and safranal (Boskabady and Farkhondeh, 2016). Like crocin (Hire et al, 2017), safranal (2-, 6-, 6-trimethyl-1, 3-cyclohexadiene-1carboxaldehyde), is known to bind to tubulin (Naghshineh et al, 2015). However, the tubulintargeted antiproliferative activity of safranal is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Safranal Inhibits HeLa Cell Viability by Perturbing the Reassembly Potential of Microtubules

Cheriyamundath

Choudhary

Lopus

2017

Phytotherapy Research

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Saffron, a spice from Crocus sativus, has been known for its health benefits and medicinal properties. Safranal is a component of saffron and is known for its antioxidant and anticancer properties. In this study, we elucidated a possible tubulin-targeted antiproliferative mechanism of action of safranal. In vitro, the compound perturbed secondary structure of tubulin without altering net microtubule polymer mass. It inhibited HeLa cell viability in a concentration-dependent manner, with minimal damage to cellular microtubules. However, it strongly inhibited recovery of microtubule network after cold-induced disassembly, indicating its ability to interfere with the nucleation potential of tubulin. Further, as the acetylation pattern of the safranal-treated microtubules revealed, unlike many tubulin-targeted agents, the compound did not appear to induce persistent stabilization of microtubules. Our data shows an unusual, tubulin-targeted antiproliferative mechanism of safranal. Copyright

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Antiproliferative Activity of Crocin Involves Targeting of Microtubules in Breast Cancer Cells

Cited by 67 publications

References 36 publications

Crocin Improves the Endothelial Function Regulated by Kca3.1 Through ERK and Akt Signaling Pathways

Crocin Improves the Endothelial Function Regulated by Kca3.1 Through ERK and Akt Signaling Pathways

Crocin inhibits the migration, invasion, and epithelial‐mesenchymal transition of gastric cancer cells via miR‐320/KLF5/HIF‐1α signaling

Safranal Inhibits HeLa Cell Viability by Perturbing the Reassembly Potential of Microtubules

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