The lipogenic LXR-SREBF1 signaling pathway controls cancer cell DNA repair and apoptosis and is a vulnerable point of malignant tumors for cancer therapy

Yang, Bo; Zhang, Bin; Cao, Zhifei; Xu, Xingdong; Huo, Zihe; Zhang, Pan; Xiang, Shufen; Zhao, Zhe; Lv, Chunping; Meng, Mei; Zhang, Gaochuan; Dong, Liang; Shi, Shucheng; Yang, Lan; Zhou, Quansheng

doi:10.1038/s41418-020-0514-3

Cited by 31 publications

(43 citation statements)

References 67 publications

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“…Triptonide exerts anti-cancer effects through down-regulation of various oncogenic genes, including βcatenin, cMyc, Notch1, LXRα, SREBF1 [30][31][32][33][34][35][36]62], particularly, triptonide directly binds to its receptor LXRα, reduces LXRα protein stability in pancreatic cancer cells, and exerts potent anti-cancer effect [36]. In the current investigation, we found that triptonide triggers degradation of Twist1 and Notch1 oncoproteins in TNBC cells.…”

Section: Discussionmentioning

confidence: 49%

“…Blots were visualized using enhanced chemiluminescence detection reagents and exposed to X-ray lm as we reported before [36].…”

Section: Western Blottingmentioning

confidence: 99%

“…The tumor xenograft mice were conducted in accordance with protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Soochow University as previously reported [33,36]. In brief, 10 7 MDA-MB-231 cells were injected into the breast of NOD-SCID female mice (18-22 g) and the mice were randomly divided into two groups (triptonide treatment group and control group, 5 mice/group).…”

Section: Tumor Xenograft Mice and Triptonide Treatmentmentioning

confidence: 99%

“…It was recently reported that triptonide exerts strong inhibitory effects on acute myeloid leukemia, lymphoma, lung cancer, gastric cancer, and pancreatic cancer via reducing cancer cell stemness and oncogenic signaling pathways, and suppressing cancer cell tumorigenesis and vasculogenic mimicry [30][31][32][33][34][35][36]. More recently, Gao B., et al reported that triptonide inhibits TNBC cell tumorigenesis via downregulation of several cancer stem cell-associated genes, up-regulation of Snail1 expression, and induction of a Snail1-associated feedback mechanism for triptonide resistance [37].…”

Section: Introductionmentioning

confidence: 99%

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Triptonide Effectively Inhibits Triple-Negative Breast Cancer Metastasis Through Concurrent Degradation Of Twist1 And Notch1 Oncoproteins

Zhang

Meng

Liu

et al. 2021

Preprint

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Background: Triple-negative breast cancer (TNBC) is highly metastatic and lethal. Due to a lack of druggable targets for this disease, there are no effective therapies in the clinic.Methods: We explored the ability of active compounds derived from natural herbs to inhibit TNBC metastasis using the methods of molecular biology, cell biology, protein chemistry, pharmacology, and xenografted mice.Results: Here, we showed that triptonide, a small molecule from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, potently inhibited TNBC cell migration, invasion, and vasculogenic mimicry, and effectively suppressed TNBC tumor growth and lung metastasis in xenografted mice with no observable toxicity. Molecular mechanistic studies revealed that triptonide strongly triggered the degradation of master epithelial-mesenchymal transition (EMT)-inducing protein Twist1 through the lysosomal system and reduced Notch1 expression and NF-κB phosphorylation, which consequently diminished the expression of pro-metastatic and angiogenic genes N-cadherin, VE-cadherin, and vascular endothelial cell growth factor receptor 2 (VEGFR2).Conclusions: Triptonide effectively suppressed TNBC cell tumorigenesis, vasculogenic mimicry, and strongly inhibited the metastasis of TNBC via degradation of Twist1 and Notch1 oncoproteins, downregulation of metastatic and angiogenic gene expression, and reduction of NF-κB signaling pathway. Our findings provide a new strategy for treating highly lethal TNBC and offer a potential new drug candidate for combatting this aggressive disease.

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Section: Discussionmentioning

confidence: 49%

“…Blots were visualized using enhanced chemiluminescence detection reagents and exposed to X-ray lm as we reported before [36].…”

Section: Western Blottingmentioning

confidence: 99%

Section: Tumor Xenograft Mice and Triptonide Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Triptonide Effectively Inhibits Triple-Negative Breast Cancer Metastasis Through Concurrent Degradation Of Twist1 And Notch1 Oncoproteins

Zhang

Meng

Liu

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…It was recently reported that triptonide exerts strong inhibitory effects on acute myeloid leukemia, lymphoma, lung cancer, gastric cancer, and pancreatic cancer via reducing cancer cell stemness and oncogenic signaling pathways, and suppressing cancer cell tumorigenesis and vasculogenic mimicry [ 32 – 38 ]. More recently, Gao et al reported that triptonide inhibits TNBC cell tumorigenesis via downregulation of several cancer stem cell-associated genes, up-regulation of Snail1 expression, and induction of a Snail1-associated feedback mechanism for triptonide resistance [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

Triptonide effectively inhibits triple-negative breast cancer metastasis through concurrent degradation of Twist1 and Notch1 oncoproteins

et al. 2021

Self Cite

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Background Triple-negative breast cancer (TNBC) is highly metastatic and lethal. Due to a lack of druggable targets for this disease, there are no effective therapies in the clinic. Methods We used TNBC cells and xenografted mice as models to explore triptonide-mediated inhibition of TNBC metastasis and tumor growth. Colony formation assay was used to quantify the tumorigenesis of TNBC cells. Wound-healing and cell trans-well assays were utilized to measure cell migration and invasion. Tube formation assay was applied to access tumor cell-mediated vasculogenic mimicry. Western blot, quantitative-PCR, immunofluorescence imaging, and immunohistochemical staining were used to measure the expression levels of various tumorigenic genes in TNBC cells. Results Here, we showed that triptonide, a small molecule from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, potently inhibited TNBC cell migration, invasion, and vasculogenic mimicry, and effectively suppressed TNBC tumor growth and lung metastasis in xenografted mice with no observable toxicity. Molecular mechanistic studies revealed that triptonide strongly triggered the degradation of master epithelial-mesenchymal transition (EMT)-inducing protein Twist1 through the lysosomal system and reduced Notch1 expression and NF-κB phosphorylation, which consequently diminished the expression of pro-metastatic and angiogenic genes N-cadherin, VE-cadherin, and vascular endothelial cell growth factor receptor 2 (VEGFR2). Conclusions Triptonide effectively suppressed TNBC cell tumorigenesis, vasculogenic mimicry, and strongly inhibited the metastasis of TNBC via degradation of Twist1 and Notch1 oncoproteins, downregulation of metastatic and angiogenic gene expression, and reduction of NF-κB signaling pathway. Our findings provide a new strategy for treating highly lethal TNBC and offer a potential new drug candidate for combatting this aggressive disease.

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Liver X receptors induce antiproliferative effects in basal‐like breast cancer

et al. 2023

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Liver X receptors (LXRs) are nuclear transcription factors important in the regulation of cholesterol transport, and glucose and fatty acid metabolism. The antiproliferative role of LXRs has been studied in a variety of malignancies and may represent a therapeutic opportunity in cancers lacking targeted therapies, such as triple‐negative breast cancer. In this study, we investigated the impact of LXR agonists alone and in combination with carboplatin in preclinical models of breast cancer. In vitro experiments revealed a dose‐dependent decrease in tumor cell proliferation in estrogen receptor‐positive breast cancer cells, whereas LXR activation in vivo resulted in an increased growth inhibitory effect in a basal‐like breast cancer model (in combination with carboplatin). Functional proteomic analysis identified differences in protein expression between responding and nonresponding models related to Akt activity, cell‐cycle progression, and DNA repair. Furthermore, pathway analysis suggested that the LXR agonist in combination with carboplatin inhibits the activity of targets of E2F transcription factors and affects cholesterol homeostasis in basal‐like breast cancer.

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The lipogenic LXR-SREBF1 signaling pathway controls cancer cell DNA repair and apoptosis and is a vulnerable point of malignant tumors for cancer therapy

Cited by 31 publications

References 67 publications

Triptonide Effectively Inhibits Triple-Negative Breast Cancer Metastasis Through Concurrent Degradation Of Twist1 And Notch1 Oncoproteins

Triptonide Effectively Inhibits Triple-Negative Breast Cancer Metastasis Through Concurrent Degradation Of Twist1 And Notch1 Oncoproteins

Triptonide effectively inhibits triple-negative breast cancer metastasis through concurrent degradation of Twist1 and Notch1 oncoproteins

Liver X receptors induce antiproliferative effects in basal‐like breast cancer

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