ER-mediated anti-tumor effects of shikonin on breast cancer

Yang, Yang; Gao, Wenya; Tao, Shiying; Wang, Yanxia; Niu, Jianzhao; Zhao, Piwen; Rao, Chenchen; Yang, Lei

doi:10.1016/j.ejphar.2019.172667

Cited by 19 publications

(14 citation statements)

References 20 publications

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“…In aspects of treatment of breast cancers, it is reported this compound showed significant anti-tumor activity for ER + breast cancer cell lines. Mechanisms demonstrated that downregulation of ERα and GPER [44], selectively downregulation of the mRNA and enzymatic activity levels of steroid sulfatase [45], as well as specifically inhibition of pyruvate kinase-M2 in MCF-7 and many drug resistance cancer cells [46,47], are the mainly involved molecular mechanisms for SKO induced breast cancer cell necrosis and apoptosis, which is significant different from the disclosed mechanisms of SKO induced cytotoxicity in MDA-MB-231 cell lines in our study. In triple negative breast cancer, we discovered the involvement of ubiquitination and degradation of cIAP1 and cIAP2 by SKO played a key role in cell necrosis and apoptosis (Fig.…”

Section: Discussioncontrasting

confidence: 77%

Shikonin promotes ubiquitination and degradation of cIAP1/2-mediated apoptosis and necrosis in triple negative breast cancer cells

et al. 2021

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Background Shikonin (SKO) is a natural naphthoquinone derived from Chinese herbal medicine Arnebiae Radix with high development potentials due to its anti-inflammatory and anti-tumor activities. Overwhelming evidences have indicated that SKO can induce both necrosis and apoptosis in cancer cells, while the mechanisms for triple negative breast cancer cells is still need to be disclosed. Methods In this study, kinds of molecular biological technologies, including flow-cytometry, Western blot, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA) as well as real-time quantitative PCR (RT-qPCR), were applied for investigation on the underlying mechanisms of SKO induced necrosis and apoptosis for MDA-MB-231 cells. Inhibitors were also used for validation ofthe key signaling pathways involved in SKO triggered necrosis and apoptosis. Results We found that SKO significantly triggered necrosis and apoptosis of MDA-MB-231 cells in both a concentration- and time-dependent manner. Mechanism studies demonstrated that SKO significantly promoted the autoubiquitination levels and facilitated the proteasome dependent degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) and cIAP2 in MDA-MB-231 cells. Autoubiquitination and degradation of cIAP1 and cIAP2 induced by SKO further led to significant decreased ubiquitination and inactivation of RIP1, which played an important role in inhibition of pro-survival and accelerating of necrosis of MDA-MB-231 cells. Treatment with proteasome inhibitor lactacystin significantly rescued the cell viability induced by treatment of SKO. Conclusions Our results demonstrate that SKO promotes the autoubiquitination and degradation of cIAP1 and cIAP2, which further induces the decrease of the ubiquitination of RIP1 to inhibit the activation of pro-survival signaling pathways and accelerate the necrosis of MDA-MB-231 cells. The disclosed mechanisms of SKO induced necrosis and apoptosis in our study is firstly reported, and it is believed that SKO could be considered as a potential candidate and further developed for the treatment of triple negative breast cancer.

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Section: Discussioncontrasting

confidence: 77%

Shikonin promotes ubiquitination and degradation of cIAP1/2-mediated apoptosis and necrosis in triple negative breast cancer cells

et al. 2021

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“…Shikonin (SHK), a naturally occurring compound, is extracted from the roots of Purple Cromwell, a kind of traditional Chinese herb used for a long time [14]. SHK has been found to exert anti-cancer effects by inducing apoptosis and inhibiting proliferation, metastasis and drug resistance of cancer cells in various malignancies including breast cancer [15][16][17]. Of particular interest, it is reported that the EMT process might be a target of SHK in reducing metastasis in some cancers, such as cervical and lung cancer [18,19].…”

Section: Introductionmentioning

confidence: 99%

Shikonin inhibits migration and invasion of triple-negative breast cancer cells by suppressing epithelial-mesenchymal transition via miR-17-5p/PTEN/Akt pathway

Bao¹,

Liu²,

Qian³

et al. 2021

J. Cancer

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Background: Triple-negative breast cancer (TNBC) is a great threat to global women's health due to its high metastatic potential. Epithelial-to-mesenchymal transition (EMT) is considered as a key event in the process of metastasis. So the pharmacological targeting of EMT might be a promising strategy in improving the therapeutic efficacy of TNBC. Here, we investigated the effect of shikonin exerting on EMT and consequently the metastasis of TNBC cells and its underlying mechanism. Methods: The invasive and migratory capacities of MDA-MB-231 and BT549 cells were tested using transwell invasion and wound healing assay. MiR-17-5p expression was examined by qRT-PCR. MiR-17-5p targeted genes were predicted with different bioinformatic algorithms from four databases (TargetScan, miRanda, PITA and picTar) and further screened by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The differential expressions of predicted genes and their correlations with miR-17-5p were identified in breast cancer patients based on The Cancer Genome Atlas (TCGA) database. The interaction between phosphatase and tensin homolog deleted on chromosome ten (PTEN) and miR-17-5p was analyzed by luciferase reporter assay. The overexpression vector and small interfering RNA were constructed to investigate the role PTEN played in metastasis and EMT regulation. The expressions of EMT markers, protein kinase B (Akt) and phospho-Akt (p-Akt) were evaluated by western blot. Results: Shikonin suppressed the migration and invasion of MDA-MB-231 and BT549 cells and meanwhile the corresponding alterations of EMT biomarkers were observed in shikonin treated MDA-MB-231 cells. Shikonin inhibited the expression of miR-17-5p, which was upregulated in breast cancer. The 3'-untranslated region (3'-UTR) of PTEN was found to be direct binding target of miR-17-5p by luciferase reporter assays. PTEN functioned as a suppressor both in the metastasis and EMT of TNBC cells. Moreover, Akt and p-Akt (Ser473) were involved in the process of inhibition in cancer cell migration, invasion and EMT by shikonin. Conclusions: Shikonin inhibits migration and invasion of TNBC cells by suppressing EMT via miR-17-5p/PTEN/Akt pathway. This suggests shikonin as a promising therapeutic agent to counteract metastasis in the TNBC patients.

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“…"Zicao" contains various naphthoquinone derivatives, of which Shikonin (SK) is one of the main active components [5]. SK possesses various similar bioactivities with "Zicao", including anti-oxidant [6], anti-inflammatory [7], and antitumor properties [8], among which the anti-tumor activity of SK has attracted much more attention. Accumulating studies demonstrated that SK can inhibit proliferation, induce apoptosis and inhibit the epithelial-to-mesenchymal transition (EMT) in various cancers, such as lung cancer [9], breast cancer [8] and cervical cancer [10].…”

Section: Introductionmentioning

confidence: 99%

“…SK possesses various similar bioactivities with "Zicao", including anti-oxidant [6], anti-inflammatory [7], and antitumor properties [8], among which the anti-tumor activity of SK has attracted much more attention. Accumulating studies demonstrated that SK can inhibit proliferation, induce apoptosis and inhibit the epithelial-to-mesenchymal transition (EMT) in various cancers, such as lung cancer [9], breast cancer [8] and cervical cancer [10]. The molecular mechanism underlying SK's anticancer effect is complicated, including inhibition of RAS-ERK, PI3K-AKT, C-MYC and the JNK pathway [11].…”

Section: Introductionmentioning

confidence: 99%

Shikonin suppresses the epithelial-to-mesenchymal transition by downregulating NHE1 in bladder cancer cells

Jia

et al. 2021

J. Cancer

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Shikonin (SK) is the major bioactive component extracted from the roots of Lithospermum erythrorhizon with anticancer activity. SK could inhibit the epithelial-to-mesenchymal transition (EMT) of cancer cells. However, the underlying mechanism is elusive. In the present study, the inhibitory activities of SK on proliferation, invasion and migration were examined in bladder cancer (BC) cells. SK potently decreased the viabilities of BC cells but showed less cytotoxicity to normal bladder epithelial cells. Moreover, SK reversed the EMT, suppressed the migration and invasion of BC cells. Intriguingly, NHE1, the major proton efflux pump, was dramatically down-regulated by SK. The EMT-inhibitory effect of SK was mediated by NHE1 down-regulation, as NHE1-overexpress alleviated while Cariporide (NHE1 inhibitor) enhanced this effect. Further, enforced alkalinization of intracellular pH (pHi) reversed the EMT-inhibitory effect of SK, indicating a key role of acidic pHi in this process. Finally, elevated NHE1 expression was observed in human bladder cancer tissues. Collectively, this research reveals a supportive effect of NHE1 and alkaline pHi on EMT. SK can suppress EMT through inhibiting NHE1 and hence inducing an acidic pHi.

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ER-mediated anti-tumor effects of shikonin on breast cancer

Cited by 19 publications

References 20 publications

Shikonin promotes ubiquitination and degradation of cIAP1/2-mediated apoptosis and necrosis in triple negative breast cancer cells

Shikonin promotes ubiquitination and degradation of cIAP1/2-mediated apoptosis and necrosis in triple negative breast cancer cells

Shikonin inhibits migration and invasion of triple-negative breast cancer cells by suppressing epithelial-mesenchymal transition via miR-17-5p/PTEN/Akt pathway

Shikonin suppresses the epithelial-to-mesenchymal transition by downregulating NHE1 in bladder cancer cells

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