Methionine affects the expression of pluripotency genes and protein levels associated with methionine metabolism in adult, fetal, and cancer stem cells

Cancer stem cells (CSCs) with self-renewal abilities endorse cellular heterogeneity, resulting in metastasis and recurrence. However, there are no promising therapeutics directed against CSCs. Herein, we found that miR-503-3p inhibited tumor growth via the regulation of CSC proliferation and self-renewal. miR-503-3p, isolated from human adipose stem cell- (ASC-) derived exosomes, suppressed initiation and progression of CSCs as determined by anchorage-dependent (colony formation) and anchorage-independent (tumorsphere formation) assays. The expression of pluripotency genes was significantly decreased in miR-503-3p-treated CSCs. Furthermore, xenografts, which received miR-503-3p, exhibited remarkably reduced tumor growth in vivo. Thus, miR-503-3p may function as a stemness-attenuating factor via cell-to-cell communications.

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The FDA-Approved Anti-Asthma Medicine Ciclesonide Inhibits Lung Cancer Stem Cells through Hedgehog Signaling-Mediated SOX2 Regulation

International Journal of Molecular Sciences ◽

10.3390/ijms21031014 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1014 ◽

Cited By ~ 5

Author(s):

Hack Sun Choi ◽

Su-Lim Kim ◽

Ji-Hyang Kim ◽

Dong-Sun Lee

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Small Interfering Rna ◽

Hedgehog Signaling ◽

Underlying Mechanism ◽

Inhibitory Effect ◽

Protein Levels ◽

Lung Cancer Stem Cells ◽

Interfering Rna

Ciclesonide is an FDA-approved glucocorticoid (GC) used to treat asthma and allergic rhinitis. However, its effects on cancer and cancer stem cells (CSCs) are unknown. Our study focuses on investigating the inhibitory effect of ciclesonide on lung cancer and CSCs and its underlying mechanism. In this study, we showed that ciclesonide inhibits the proliferation of lung cancer cells and the growth of CSCs. Similar glucocorticoids, such as dexamethasone and prednisone, do not inhibit CSC formation. We show that ciclesonide is important for CSC formation through the Hedgehog signaling pathway. Ciclesonide reduces the protein levels of GL1, GL2, and Smoothened (SMO), and a small interfering RNA (siRNA) targeting SMO inhibits tumorsphere formation. Additionally, ciclesonide reduces the transcript and protein levels of SOX2, and an siRNA targeting SOX2 inhibits tumorsphere formation. To regulate breast CSC formation, ciclesonide regulates GL1, GL2, SMO, and SOX2. Our results unveil a novel mechanism involving Hedgehog signaling and SOX2 regulated by ciclesonide in lung CSCs, and also open up the possibility of targeting Hedgehog signaling and SOX2 to prevent lung CSC formation.

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Abstract LB-247: Targeting methionine metabolism to eradicate cancer stem cells

10.1158/1538-7445.am2018-lb-247 ◽

2018 ◽

Cited By ~ 1

Author(s):

Elena Strekalova ◽

Dmitry Malin ◽

Dominik Hoelper ◽

Peter Lewis ◽

Vincent Cryns

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Methionine Metabolism

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Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Journal of Experimental Medicine ◽

10.1084/jem.20142288 ◽

2015 ◽

Vol 212 (12) ◽

pp. 2057-2075 ◽

Cited By ~ 41

Author(s):

Aurélie Ladang ◽

Francesca Rapino ◽

Lukas C. Heukamp ◽

Lars Tharun ◽

Kateryna Shostak ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Ex Vivo ◽

Tumor Initiation ◽

Normal Epithelium ◽

Intestinal Epithelia ◽

Protein Levels ◽

Radiation Induced ◽

Sox9 Protein

Tumor initiation in the intestine can rapidly occur from Lgr5+ crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5+/Dclk1+/Sox9+ cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5+ cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5+/Dclk1+/Sox9+ cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5+/Dclk1+ cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1+ cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine.

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Initial first-in-human phase 1 results of PTC596, a novel small molecule that targets cancer stem cells (CSCs) by reducing BMI1 protein levels

Annals of Oncology ◽

10.1093/annonc/mdw368.27 ◽

2016 ◽

Vol 27 ◽

pp. vi122 ◽

Cited By ~ 2

Author(s):

G. Shapiro ◽

J. Infante ◽

T.M. Bauer ◽

A. Prawira ◽

P. Bedard ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Small Molecule ◽

Phase 1 ◽

Protein Levels

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Modulation of LXR signaling altered the dynamic activity of human colon adenocarcinoma cancer stem cells in vitro

Cancer Cell International ◽

10.1186/s12935-021-01803-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hassan Dianat-Moghadam ◽

Mostafa Khalili ◽

Mohsen Keshavarz ◽

Mehdi Azizi ◽

Hamed Hamishehkar ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Abc Transporters ◽

Flow Cytometric Analysis ◽

Metabolic Enzymes ◽

Colorectal Cancers ◽

Control Group ◽

Dependent Manner ◽

Protein Levels ◽

And Migration

Abstract Background The expansion and metastasis of colorectal cancers are closely associated with the dynamic growth of cancer stem cells (CSCs). This study aimed to explore the possible effect of LXR (a regulator of glycolysis and lipid hemostasis) in the tumorgenicity of human colorectal CD133 cells. Methods Human HT-29 CD133+ cells were enriched by MACS and incubated with LXR agonist (T0901317) and antagonist (SR9243) for 72 h. Cell survival was evaluated using MTT assay and flow cytometric analysis of Annexin-V. The proliferation rate was measured by monitoring Ki-67 positive cells using IF imaging. The modulation of LXR was studied by monitoring the activity of all factors related to ABC transporters using real-time PCR assay and western blotting. Protein levels of metabolic enzymes such as PFKFB3, GSK3β, FASN, and SCD were also investigated upon treatment of CSCs with LXR modulators. The migration of CSCs was monitored after being exposed to LXR agonist using scratch and Transwell insert assays. The efflux capacity was measured using hypo-osmotic conditions. The intracellular content of reactive oxygen species was studied by DCFH-DA staining. Results Data showed incubation of CSCs with T0901317 and SR9243 reduced the viability of CD133 cells in a dose-dependent manner compared to the control group. The activation of LXR up-regulated the expression and protein levels of ABC transporters (ABCA1, ABCG5, and ABCG8) compared to the non-treated cells (p < 0.05). Despite these effects, LXR activation suppressed the proliferation, clonogenicity, and migration of CD133 cells, and increased hypo-osmotic fragility (p < 0.05). We also showed that SR9243 inhibited the proliferation and clonogenicity of CD133 cells through down-regulating metabolic enzymes PFKFB3, GSK3β, FASN, and SCD as compared with the control cells (p < 0.05). Intracellular ROS levels were increased after the inhibition of LXR by SR9243 (p < 0.05). Calling attention, both T0901317 and SR9243 compounds induced apoptotic changes in cancer stem cells (p < 0.05). Conclusions The regulation of LXR activity can be considered as a selective targeting of survival, metabolism, and migration in CSCs to control the tumorigenesis and metastasis in patients with advanced colorectal cancers.

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Allicin Could Potentially Alleviate Oral Cancer Pain by Inhibiting “Pain Mediators” TNF-alpha, IL-8, and Endothelin

Current Issues in Molecular Biology ◽

10.3390/cimb43010016 ◽

2021 ◽

Vol 43 (1) ◽

pp. 187-196

Author(s):

Abdulwahab H. Alamir ◽

Shankargouda Patil

Keyword(s):

Stem Cells ◽

Oral Cancer ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Tnf Alpha ◽

Protein Levels ◽

Gene And Protein Expression ◽

Promising Treatment ◽

Oral Cancer Cells

To evaluate the effects of allicin on mediators of pain secreted by oral cancer cells in vitro, single-cell suspensions were prepared by enzymatic method from oral squamous cell carcinoma (OSCC). Cancer stem cells were isolated by the CD133+ selection method with magnetic cell sorting. Stemness markers were checked in both cancer cells and cancer stem cells by RT-PCR. Comparative analysis of pain mediators TNF-alpha, IL-8, and endothelin at both RNA and protein levels for normal epithelial cells, cancer cells, and cancer stem cells was carried out with and without allicin treatment. CD133 and CD44 expression levels were checked in cancer cells and cancer stem cells flow cytometrically. Allicin inhibited both gene and protein expression of TNF-alpha, IL-8, and endothelin in both cancer cells and cancer stem cells. Allicin is more likely to be a promising treatment in alleviating the levels of pain and inflammation in OSCCs.

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Disruption of the NF-κB/IL-8 Signaling Axis by Sulconazole Inhibits Human Breast Cancer Stem Cell Formation

Cells ◽

10.3390/cells8091007 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1007 ◽

Cited By ~ 9

Author(s):

Hack Sun Choi ◽

Ji-Hyang Kim ◽

Su-Lim Kim ◽

Dong-Sun Lee

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cell Formation ◽

Tumor Initiating Cells ◽

Self Renewal ◽

Mammosphere Formation ◽

Protein Levels ◽

New Findings ◽

Poor Outcomes

Breast cancer stem cells (BCSCs) are tumor-initiating cells that possess the capacity for self-renewal. Cancer stem cells (CSCs) are responsible for poor outcomes caused by therapeutic resistance. In our study, we found that sulconazole—an antifungal medicine in the imidazole class—inhibited cell proliferation, tumor growth, and CSC formation. This compound also reduced the frequency of cells expressing CSC markers (CD44high/CD24low) as well as the expression of another CSC marker, aldehyde dehydrogenase (ALDH), and other self-renewal-related genes. Sulconazole inhibited mammosphere formation, reduced the protein level of nuclear NF-κB, and reduced extracellular IL-8 levels in mammospheres. Knocking down NF-κB expression using a p65-specific siRNA reduced CSC formation and secreted IL-8 levels in mammospheres. Sulconazole reduced nuclear NF-κB protein levels and secreted IL-8 levels in mammospheres. These new findings show that sulconazole blocks the NF-κB/IL-8 signaling pathway and CSC formation. NF-κB/IL-8 signaling is important for CSC formation and may be an important therapeutic target for BCSC treatment.

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SKP1 promotes YAP-mediated colorectal cancer stemness via suppressing RASSF1

10.21203/rs.3.rs-29004/v2 ◽

2020 ◽

Author(s):

Cong Tian ◽

Tingyuan Lang ◽

Jiangfeng Qiu ◽

Kun Han ◽

Lei Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Drug Target ◽

Self Renewal ◽

Protein Levels ◽

Colorectal Cancer Cells ◽

Underlying Mechanisms ◽

And Migration

Abstract Background: Cancer stem cells (CSCs) have been recognized as an important drug target, however, the underlying mechanisms have not been fully understood. SKP1 is a traditional drug target for cancer therapy, while, whether SKP1 promotes colorectal cancer (CRC) stem cells (CRC-SCs) and the underlying mechanisms have remained elusive.Methods: Human CRC cell lines HCT-116 and HT-29 and primary human colorectal cancer cells were used in this study. Gene manipulation was performed by lentivirus system. The mRNA and protein levels were examined by qRT-PCR and western blot, respectively. Sphere formation and transwell assay were employed for examination of sphere-forming and migration capacities. The self-renewal capacity was determined by limiting dilution assay. The tumorigenicity was examined by xenograft model. The transcriptional activities of the promoters were examined by luciferase reporter assay. Co-immunoprecipitation assay was used to test protein-protein interaction. The transcription and protein-DNA interaction were examined by nuclear run-on and ChIP-PCR assay. The relationship between gene expression and survival was analyzed by Kaplan-meier analysis. The correlation between two genes was analyzed by Spearman analysis. Data are represented as mean ± s.d. and the significance was determined by Student’s t-test.Results: SKP1 is upregulated in colorectal cancer stem cells and predicts poor prognosis of colon cancer patients. Overexpression of SKP1 promotes the sphere-forming and migration capacities as well as self-renewal of CRC cells, and upregulates the expression of CSCs markers. In contrast, SKP1 depletion produces the opposite effects. SKP1 strengthens YAP activity and knockdown of YAP abolished the effect of SKP1 on the stemness of colorectal cancer cells. SKP1 suppresses RASSF1 at both mRNA and protein levels and overexpression of RASSF1 abolished the effect of SKP1.Conclusion: Our results demonstrated that SKP1 suppresses RASSF1 at both mRNA and protein level, attenuates Hippo signaling, activates YAP, and thereby promoting the stemness of CRC cells. Our works thus revealed a novel underlying mechanism of CRC-SCs maintenance and suggested a novel drug target for eradicating CRC-SCs.

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SKP1 promotes YAP-mediated colorectal cancer stemness via suppressing RASSF1

10.21203/rs.3.rs-29004/v1 ◽

2020 ◽

Author(s):

Cong Tian ◽

Tingyuan Lang ◽

Jiangfeng Qiu ◽

Kun Han ◽

Lei Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Drug Target ◽

Human Colorectal Cancer ◽

Protein Levels ◽

Colorectal Cancer Cells ◽

And Migration ◽

Colorectal Cancer Stem Cells

Abstract Background: Cancer stem cells have been recognized as an important drug target, however, the mechanisms underlying the maintenance of cancer stem cells have not been fully understood. SKP1 is a traditional drug target for cancer therapy, while, whether SKP1 could be a target for eradicating cancer stem cells remains elusive.Methods: Human colorectal cancer cell lines HCT-116 and HT-29 and primary human colorectal cancer cells were used in this study. Gene manipulation was performed by lentivirus system. The mRNA and protein levels were examined by qRT-PCR and western blot, respectively. Sphere formation and transwell assay were employed for examination of sphere-forming and migration capacities. The tumorigenicity was examined by xenograft model. The transcriptional activities of the promoters were examined by luciferase reporter assay. Co-immunoprecipitation assay was used to test protein-protein interaction. The relationship between gene expression and survival was analyzed by Kaplan-meier analysis. The correlation between two genes was analyzed by Spearman analysis. Data are represented as mean ± s.d. and the significance was determined by Student’s t-test.Results: SKP1 is upregulated in colorectal cancer stem cells and predicts poor prognosis of colon cancer patients. Overexpression of SKP1 promotes the sphere-forming and migration capacities of colorectal cancer stem cells, and upregulates the expression of cancer stem cell markers. In contrast, SKP1 depletion produces the opposite effects. SKP1 strengthens YAP activity and knockdown of YAP abolished the effect of SKP1 on the stemness of colorectal cancer cells. SKP1 suppresses RASSF1 at both mRNA and protein levels and overexpression of RASSF1 abolished the effect of SKP1.Conclusion: In summary, our results demonstrated that SKP1 suppresses RASSF1 at both mRNA and protein level, attenuates Hippo signaling, activates YAP, and thereby promoting the stemness of colorectal cancer stem cells. Our works thus revealed a novel underlying mechanism of colorectal cancer stem cell maintenance and suggested a novel drug target for eradicating colorectal cancer stem cells.

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