scholarly journals Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Haiying Yue ◽  
Dongning Huang ◽  
Li Qin ◽  
Zhiyong Zheng ◽  
Li Hua ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Progression ◽  
Cell Cycle Distribution ◽  
Lung Cancer Stem Cells ◽  
Sphere Formation

Lung cancer stem cells are a subpopulation of cells critical for lung cancer progression, metastasis, and drug resistance. Thioridazine, a classical neurological drug, has been reported with anticancer ability. However, whether thioridazine could inhibit lung cancer stem cells has never been studied. In our current work, we used different dosage of thioridazine to test its effect on lung cancer stem cells sphere formation. The response of lung cancer stem cells to chemotherapy drug with thioridazine treatment was measured. The cell cycle distribution of lung cancer stem cells after thioridazine treatment was detected. The in vivo inhibitory effect of thioridazine was also measured. We found that thioridazine could dramatically inhibit sphere formation of lung cancer stem cells. It sensitized the LCSCs to chemotherapeutic drugs 5-FU and cisplatin. Thioridazine altered the cell cycle distribution of LCSCs and decreased the proportion of G0 phase cells in lung cancer stem cells. Thioridazine inhibited lung cancer stem cells initiated tumors growth in vivo. This study showed that thioridazine could inhibit lung cancer stem cells in vitro and in vivo. It provides a potential drug for lung cancer therapy through targeting lung cancer stem cells.

scholarly journals The Role and Molecular Mechanism of SLC34A2 in Stemness Maintenance of CD44+CD166+ Lung Cancer Stem Cells (LCSCs) with AT-II cells’ characteristics

2021 ◽  
Author(s):  
Yan Yang ◽  
Qiang Pu ◽  
Hu Liao ◽  
Yue Yuan ◽  
Xueting Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Malignant Transformation ◽  
Lung Tumor ◽  
Alveolar Epithelium ◽  
Migration And Invasion ◽  
Lung Cancer Stem Cells

Abstract Background Evidence showed some non-small cell lung cancers (NSCLCs) had the type II alveolar epithelium cells’(AT-II cells) characteristics, and AT-II cells were a kind of original stem cells of NSCLCs. But how AT-II cells malignantly transformed into NSCLCs was unclear. Recent evidence indicated SLC34A2 was critical in the development of AT-II cells, and SLC34A2 might be a new gene in the initiation of NSCLCs. However, whether SLC34A2 participated in the malignant transformation of AT-II cells remained unknown. The exact role and mechanism of SLC34A2 in the initiation of NSCLCs needed to be further investigated. Methods The expression of Napi-IIb (encoded by SLC34A2) in the NSCLC cells was compared with that in AT-II cells using immunohistochemistry (IHC). Also coexpression of CD44 and CD166 was detected in these NSCLCs tissues by IHC. Then the CD44+CD166+ cells were sorted from lung tumor spheres by FACS. They were assessed by sphere, proliferation and tumorgenicity assay. Besides, their expression of surfactants C(SP-C) was stained by IHC. Next, the role and mechanism of SLC34A2 in CD44+CD166+ lung cancer stem cells were explored by siRNA-mediated SLC34A2 knockdown, related pathway pharmacological inhibition or activation. In vitro findings were furtherly validated in vivo and NSCLCs samples. Results The expression of SLC34A2 was downregulated in NSCLCs cells compared with AT-II cells in clinic samples. Then the CD44+CD166+ population was identified as CD44+CD166+ lung cancer stem cells (LCSCs). And LCSCs showed abundant expression of SP-C, the hallmark of AT-II cells. Higher expression of SLC34A2 was found in LCSCs compared to their origin NSCLC cells. Additionally, the expression of SLC34A2 was decreased after LCSCs were differentiated, and the morphology of the differentiated cells from LCSCs was similar to their origin NSCLC cells. Knockdown SLC34A2 made declined abilities of self-renewal, drug-resistance, migration and invasion in vitro as well as tumorigenicity in vivo in LCSCs. And SLC34A2 could maintain stemness of LCSCs via PI3K/AKT/STAT3/Sox2 axis. Besides, the connection between SLC34A2 maintaining stemness of lung cancer stem cells and PI3K/AKT/STAT3/Sox2 axis was also validated in vivo and in clinic samples. Conclusions For the first time, we illustrated the expression of SLC34A2 was downregulated in NSCLCs cells compared with AT-II cells. We discovered the downregulated expression of SLC34A2 performed a vital role in the malignant transformation of AT-II cells into NSCLCs. And SLC34A2 could maintain stemness of CD44+CD166+ lung cancer stem cells, which were with AT-II cell’s characteristic, via PI3K/AKT/STAT3/Sox2 axis. It had important significance in the revelation of a new mechanism for the initiation of NSCLCs.

scholarly journals ID: 1023 All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth

2017 ◽  
Vol 4 (S) ◽  
pp. 98
Author(s):  
P H Nguyen ◽  
J Giraud ◽  
C Staedel ◽  
L Chambonnier ◽  
P Dubus ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Gastric Carcinoma ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
3D Culture ◽  
All Trans Retinoic Acid

Gastric carcinoma is the third leading cause of cancer-related death worldwide. This cancer, most of the time metastatic, is essentially treated by surgery associated with conventional chemotherapy, and has a poor prognosis. The existence of cancer stem cells (CSC) expressing CD44 and a high aldehyde dehydrogenase (ALDH) activity has recently been demonstrated in gastric carcinoma and has opened new perspectives to develop targeted therapy. In this study, we evaluated the effects of all-transretinoic acid (ATRA) on CSCs in human gastric carcinoma. ATRA effects were evaluated on the proliferation and tumorigenic properties of gastric carcinoma cells from patient-derived tumors and cell lines in conventional 2D cultures, in 3D culture systems (tumorsphere assay) and in mouse xenograft models. ATRA inhibited both tumorspheres initiation and growth in vitro, which was associated with a cell-cycle arrest through the upregulation of cyclin-dependent kinase (CDK) inhibitors and the downregulation of cell-cycle progression activators. More importantly, ATRA downregulated the expression of the CSC markers CD44 and ALDH as well as stemness genes such as Klf4 and Sox2 and induced differentiation of tumorspheres. Finally, 2 weeks of daily ATRA treatment were sufficient to inhibit gastric tumor progression in vivo, which was associated with a decrease in CD44, ALDH1, Ki67 and PCNA expression in the remaining tumor cells. Administration of ATRA appears to be a potent strategy to efficiently inhibit tumor growth and more importantly to target gastric CSCs in both intestinal and diffuse types of gastric carcinoma.

Aldehyde dehydrogenase activity in serous ovarian carcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15577-e15577
Author(s):  
Petra M. Bareiss ◽  
Tanja N. Fehm ◽  
Anna Fischer ◽  
Matthias Grauer ◽  
Philipp Kokorsch ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Ovarian Carcinoma ◽  
Aldehyde Dehydrogenase ◽  
Cell Cycle Distribution ◽  
Aldh Activity ◽  
Serous Ovarian Carcinoma ◽  
Aldh1 Expression

e15577 Background: Only specific subpopulations of tumor cells, so called cancer stem cells (CSC) may initiate and maintain tumors. The phenotype and molecular properties of ovarian CSC remain elusive. Aldehyde dehydrogenase (ALDH) activity characterizes (cancer) stem cells in different tissues and has been associated with ovarian CSC (Silva et al, 2011; Kryczek et al, 2012). Contradictory results have been reported on ALDH1 expression and prognosis in ovarian carcinoma. In this study, we explore the role of ALDH in serous ovarian carcinoma (SOC). Methods: Aldefluor-staining was used to assess ALDH activity in different ovarian carcinoma cell-lines and patient samples. ALDH+ and ALDH- cells isolated by FACS and ALDH1 versus control siRNA treated cells were analyzed in sphere forming, proliferation, BrdU and cell cycle assays. In vivo tumorigenicity assays including serial re-transplantations were performed in NOD/SCID/IL2Rγnull mice. ALDH1 and Ki67 expression were assessed immunohistochemically on a tissue microarray of 152 SOC samples. Results: ALDH+ cells formed more tumor spheres than ALDH- cells from the OVCAR-3 cell line and primary SOC and larger spheres (> 5.000 µm²) developed solely from ALDH+ cells. However, in vivo both cell fractions gave rise to tumors. Tumors contained both ALDH+ and ALDH- cells irrespective of the starting population. Notably, ALDH+ cells generated tumors more rapidly and induced larger tumors, suggesting a higher proliferative capacity. Immunohistochemical analysis of a larger cohort of SOC patients confirmed association of ALDH1 expression with the proliferation marker Ki67 (p=0.007). Surprisingly, co-stainings revealed that ALDH1 positive cells were mostly Ki67 negative and cell cycle synchronisation experiments using different agents showed ALDH induction in G0-enriched OVCAR-3 cells. However, inhibition of ALDH by treatment with three distinct siRNAs against ALDH1 did not alter cell cycle distribution. Conclusions: Our data suggest that ALDH is a correlative marker indicating, but not actively sustaining a quiescent stem-cell like state in SOC. Upon exit from G0, ALDH+ cells lose ALDH expression and induce a proliferative response.

scholarly journals Long non-coding RNA NORAD promotes pancreatic cancer stem cell proliferation and self-renewal by blocking microRNA-202-5p-mediated ANP32E inhibition

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yu-Shui Ma ◽  
Xiao-Li Yang ◽  
Yu-Shan Liu ◽  
Hua Ding ◽  
Jian-Jun Wu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Viability ◽  
Luciferase Reporter ◽  
Cell Cycle Distribution ◽  
Loss Of Function ◽  
Self Renewal

Abstract Background Cancer stem cells (CSCs) are key regulators in the processes of tumor initiation, progression, and recurrence. The mechanism that maintains their stemness remains enigmatic, although the role of several long noncoding RNAs (lncRNAs) has been highlighted in the pancreatic cancer stem cells (PCSCs). In this study, we first established that PCSCs overexpressing lncRNA NORAD, and then investigated the effects of NORAD on the maintenance of PCSC stemness. Methods Expression of lncRNA NORAD, miR-202-5p and ANP32E in PC tissues and cell lines was quantified after RNA isolation. Dual-luciferase reporter assay, RNA pull-down and RIP assays were performed to verify the interactions among NORAD, miR-202-5p and ANP32E. We then carried out gain- and loss-of function of miR-202-5p, ANP32E and NORAD in PANC-1 cell line, followed by measurement of the aldehyde dehydrogenase activity, cell viability, apoptosis, cell cycle distribution, colony formation, self-renewal ability and tumorigenicity of PC cells. Results LncRNA NORAD and ANP32E were upregulated in PC tissues and cells, whereas the miR-202-5p level was down-regulated. LncRNA NORAD competitively bound to miR-202-5p, and promoted the expression of the miR-202-5p target gene ANP32E thereby promoting PC cell viability, proliferation, and self-renewal ability in vitro, as well as facilitating tumorigenesis of PCSCs in vivo. Conclusion Overall, lncRNA NORAD upregulates ANP32E expression by competitively binding to miR-202-5, which accelerates the proliferation and self-renewal of PCSCs.

scholarly journals Reck-Notch1 Signaling Mediates miR-221/222 Regulation of Lung Cancer Stem Cells in NSCLC

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuefan Guo ◽  
Guangxue Wang ◽  
Zhongrui Wang ◽  
Xin Ding ◽  
Lu Qian ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cell Proliferation ◽  
Mammosphere Formation ◽  
Notch1 Signaling ◽  
Cancer Initiation ◽  
Direct Target Gene ◽  
Lung Cancer Stem Cells

Cancer stem cells (CSCs) contribute to the cancer initiation, metastasis and drug resistance in non-small cell lung cancer (NSCLC). Herein, we identified a miR-221/222 cluster as a novel regulator of CSCs in NSCLC. Targeted overexpression or knockdown of miR-221/222 in NSCLC cells revealed the essential roles of miR-221/222 in regulation of lung cancer cell proliferation, mammosphere formation, subpopulation of CD133+ CSCs and the expression of stemness genes including OCT4, NANOG and h-TERT. The in vivo animal study showed that overexpression of miR-221/222 significantly enhanced the capacity of lung cancer cells to develop tumor and grow faster, indicating the importance of miR-221/222 in tumorigenesis and tumor growth. Mechanistically, Reck was found to be a key direct target gene of miR-221/222 in NSCLC. Overexpression of miR-221/222 significantly suppressed Reck expression, activated Notch1 signaling and increased the level of NICD. As an activated form of Notch1, NICD leads to enhanced stemness in NSCLC cells. In addition, knockdown of Reck by siRNA not only mimicked miR-221/222 effects, but also demonstrated involvement of Reck in the miR-221/222-induced activation of Notch1 signaling, verifying the essential roles of the miR-221/222-Reck-Notch1 axis in regulating stemness of NSCLC cells. These findings uncover a novel mechanism by which lung CSCs are significantly manipulated by miR-221/222, and provide a potential therapeutic target for the treatment of NSCLC.

scholarly journals GLUT-1 siRNA Enhances Radiosensitization Of Laryngeal Cancer Stem Cells Via Enhanced DNA Damage, Cell Cycle Redistribution, And Promotion Of Apoptosis In Vitro And In Vivo

2019 ◽  
Vol Volume 12 ◽  
pp. 9129-9142 ◽  
Author(s):  
Jiang-Tao Zhong ◽  
Qi Yu ◽  
Shui-Hong Zhou ◽  
Er Yu ◽  
Yang-Yang Bao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Cancer Stem Cells ◽  
Laryngeal Cancer ◽  
Damage Cell ◽  
Glut 1

scholarly journals miR-21 modulates the effect of EZH2 on the biological behavior of human lung cancer stem cells in vitro

Oncotarget ◽  
2017 ◽  
Vol 8 (49) ◽  
pp. 85442-85451 ◽  
Author(s):  
Hui Xia ◽  
Wen Zhang ◽  
Baoshi Zhang ◽  
Yingnan Zhao ◽  
Yunlong Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Human Lung ◽  
Biological Behavior ◽  
Human Lung Cancer ◽  
Lung Cancer Stem Cells

scholarly journals Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Haiyang Zhang ◽  
Meng Wang ◽  
Yi He ◽  
Ting Deng ◽  
Rui Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cells ◽  
Cell Death ◽  
Cancer Stem Cells ◽  
In Vivo Experiments ◽  
Gastric Cancer Stem Cells ◽  
Nuclear Ribonucleoprotein ◽  
Sphere Formation

AbstractCancer stem cells (CSCs) are an important cause of tumor recurrence and drug resistance. As a new type of cell death that relies on iron ions and is strictly regulated by intracellular and extracellular signals, the role of ferroptosis in tumor stem cells deserves extensive attention. Mass spectrum was applied to screen for ferroptosis-related proteins in gastric cancer (GC). Sphere-formation assay was used to estimate the stemness of gastric cancer stem cells (GCSCs). Exosomal lnc-ENDOG-1:1 (lncFERO) was isolated by ultracentrifugation. Ferroptosis was induced by erastin and was assessed by detecting lipid ROS, mitochondrial membrane potential, and cell death. Furthermore, a series of functional in vitro and in vivo experiments were conducted to evaluate the effects of lncFERO on regulating ferroptosis and chemosensitivity in GCSCs. Here, we showed that stearoyl-CoA-desaturase (SCD1) played a key role in regulating lipid metabolism and ferroptosis in GCSCs. Importantly, exosomal lncFERO (exo-lncFERO) derived from GC cells was demonstrated to promote SCD1 expression by directly interacting with SCD1 mRNA and recruiting heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which resulted in the dysregulation of PUFA levels and the suppression of ferroptosis in GCSCs. Moreover, we found that hnRNPA1 was also involved in lncFERO packing into exosomes in GC cells, and both in vitro and in vivo data suggested that chemotoxicity induced lncFERO secretion from GC cells by upregulating hnRNPA1 expression, leading to enhanced stemness and acquired chemo-resistance. All these data suggest that GC cells derived exo-lncFERO controls GCSC tumorigenic properties through suppressing ferroptosis, and targeting exo-lncFERO/hnRNPA1/SCD1 axis combined with chemotherapy could be a promising CSC-based strategy for the treatment of GC.

Sign in / Sign up

Export Citation Format

Share Document