Cancer stem cells and escape from drug-induced premature senescence in human lung tumor cells: Implications for drug resistance and in vitro drug screening models

e23018 Background: More than 1.6 million cases of breast cancer (BC) are diagnosed annually worldwide. Despite advances in diagnoses and treatment, BC remains the third leading cause of death in women. Metastases and chemotherapy resistance are the main factors contributing to BC mortality. The ability of tumor cells to overcome the drug-induced growth inhibition is now linked to a unique population of cancer initiating tumor cells, often referred as cancer stem cells (CSC). CSC represent a small fraction of tumor cells, therefore, currently used isolation protocols have a low yield and are poorly reproducible, hampering research on the role of these cells in cancer chemoresistance. We propose a novel approach to generate large quantities of CSC-like cells by genetic reprogramming of non-stem cancer cells. Methods: We postulate that CSC-enriched cell line can be developed in vitro by upregulating of proteins controlling cancer cell pluripotency including Oct4, Sox2, NANOG, KLF4 and c-Myc. Increased transcriptional and translational activity of these genes in MCF-7 cells was demonstrated by real time-PCR and Western blot. Proliferation and migration of cells overexpressing Oct4, Sox2, NANOG, KLF4 and c-Myc were analyzed as well. Also, changes in CSC population counts and their sensitivity to chemotherapy were investigated using sphere formation assay. Results: We found that cell proliferation rate was correlated with the expression level of c-Myc and Oct4. Increased CSC counts were found in cells with overexpressed Oct4 (62.7%), KLF4 (97%) and NANOG (121.3%) proteins as compared to the parental cells. Overexpression of SOX2, NANOG and KLF4 significantly increased CSC resistance to docetaxel (83,3±6,8; 93,3±4,5 and 80,3±5,0 spheres respectively) when compared to the original cells (48,3±3,0 spheres). Conclusions: We conclude that overexpression of pluripotency proteins Oct4, Sox2, NANOG, KLF4 and c-Myc changes the CSC counts and proliferation capacity of BC cells. Acknowledgements: The study was funded by RFBR, according to the research project No. 16-34-60210 mol_а_dk, and by Russian Government Program of Competitive Growth of Kazan Federal University.

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Reversal of drug resistance in MRP overexpressing multidrug resistant human lung tumor cells

Anti-Cancer Drugs ◽

10.1097/00001813-199409001-00070 ◽

1994 ◽

Vol 5 ◽

pp. 30 ◽

Cited By ~ 5

Author(s):

C HM Versantvoort ◽

H J Broxterman ◽

T Bagrij ◽

P R Twentyman

Keyword(s):

Drug Resistance ◽

Tumor Cells ◽

Human Lung ◽

Lung Tumor ◽

Multidrug Resistant ◽

Human Lung Tumor

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Computational modeling reveals MAP3K8 as mediator of resistance to vemurafenib in thyroid cancer stem cells

Bioinformatics ◽

10.1093/bioinformatics/bty969 ◽

2018 ◽

Vol 35 (13) ◽

pp. 2267-2275 ◽

Cited By ~ 9

Author(s):

Fiorenza Gianì ◽

Giulia Russo ◽

Marzio Pennisi ◽

Laura Sciacca ◽

Francesco Frasca ◽

...

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Drug Resistance ◽

Thyroid Cancer ◽

Cancer Stem Cells ◽

Braf Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Braf V600e ◽

Supplementary Information

Abstract Motivation Val600Glu (V600E) mutation is the most common BRAF mutation detected in thyroid cancer. Hence, recent research efforts have been performed trying to explore several inhibitors of the V600E mutation-containing BRAF kinase as potential therapeutic options in thyroid cancer refractory to standard interventions. Among them, vemurafenib is a selective BRAF inhibitor approved by Food and Drug Administration for clinical practice. Unfortunately, vemurafenib often displays limited efficacy in poorly differentiated and anaplastic thyroid carcinomas probably because of intrinsic and/or acquired resistance mechanisms. In this view, cancer stem cells (CSCs) may represent a possible mechanism of resistance to vemurafenib, due to their self-renewal and chemo resistance properties. Results We present a computational framework to suggest new potential targets to overcome drug resistance. It has been validated with an in vitro model based upon a spheroid-forming method able to isolate thyroid CSCs that may mimic resistance to vemurafenib. Indeed, vemurafenib did not inhibit cell proliferation of BRAF V600E thyroid CSCs, but rather stimulated cell proliferation along with a paradoxical over-activation of ERK and AKT pathways. The computational model identified a fundamental role of mitogen-activated protein kinase 8 (MAP3K8), a serine/threonine kinase expressed in thyroid CSCs, in mediating this drug resistance. To confirm model prediction, we set a suitable in vitro experiment revealing that the treatment with MAP3K8 inhibitor restored the effect of vemurafenib in terms of both DNA fragmentation and poly (ADP-ribose) polymerase cleavage (apoptosis) in thyroid CSCs. Moreover, MAP3K8 expression levels may be a useful marker to predict the response to vemurafenib. Availability and implementation The model is available in GitHub repository visiting the following URL: https://github.com/francescopappalardo/MAP3K8-Thyroid-Spheres-V-3.0. Supplementary information Supplementary data are available at Bioinformatics online.

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Expression of Potential Cancer Stem Cell Marker ABCG2 is Associated with Malignant Behaviors of Hepatocellular Carcinoma

Gastroenterology Research and Practice ◽

10.1155/2013/782581 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 22

Author(s):

Guang Zhang ◽

Zhongxia Wang ◽

Weihuan Luo ◽

Hongbo Jiao ◽

Junhua Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Expression Level ◽

Stem Cell Marker ◽

Migration And Invasion ◽

Close Relationship ◽

A Minor

Background. Despite improvement in treatment, the prognosis of hepatocellular carcinoma (HCC) remains disastrous. Cancer stem cells (CSCs) may be responsible for cancer malignant behaviors. ATP-binding cassette, subfamily G, member 2 (ABCG2) is widely expressed in both normal and cancer stem cells and may play an important role in cancer malignant behaviors.Methods. The expression of ABCG2 in HCC tissues and SMMC-7721 cells was examined, and the relevance of ABCG2 expression with clinical characteristics was analyzed. ABCG2+ and ABCG2− cells were sorted, and the potential of tumorigenicity was determined. Expression level of ABCG2 was manipulated by RNA interference and overexpression. Malignant behaviors including proliferation, drug resistance, migration, and invasion were studied in vitro.Results. Expression of ABCG2 was found in a minor group of cells in HCC tissues and cell lines. ABCG2 expression showed tendencies of association with unfavorable prognosis factors. ABCG2 positive cells showed a superior tumorigenicity. Upregulation of ABCG2 enhanced the capacity of proliferation, doxorubicin resistance, migration, and invasion potential, while downregulation of ABCG2 significantly decreased these malignant behaviors.Conclusion. Our results indicate that ABCG2 is a potential CSC marker for HCC. Its expression level has a close relationship with tumorigenicity, proliferation, drug resistance, and metastasis ability.

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Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1α in vitro

Oncology Reports ◽

10.3892/or.2016.4813 ◽

2016 ◽

Vol 36 (1) ◽

pp. 428-440 ◽

Cited By ~ 11

Author(s):

WEN-JING WANG ◽

HUA SUI ◽

CONG QI ◽

QI LI ◽

JIE ZHANG ◽

...

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Ursolic Acid ◽

Hypoxia Inducible Factor ◽

Ovarian Cancer Stem Cells ◽

Hypoxia Inducible Factor 1Α

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INTERLEUKIN-4 INHIBITS GROWTH OF A HUMAN LUNG-TUMOR CELL-LINE IN-VITRO AND HAS THERAPEUTIC ACTIVITY AGAINST XENOGRAFTS OF THIS CELL-LINE IN-VIVO

International Journal of Oncology ◽

10.3892/ijo.3.2.167 ◽

1993 ◽

Author(s):

MS TOPP ◽

M KOENIGSMANN ◽

A MIRESLUIS ◽

D OBERBERG ◽

F EITELBACH ◽

...

Keyword(s):

Cell Line ◽

Human Lung ◽

Lung Tumor ◽

Tumor Cell Line ◽

Interleukin 4 ◽

Therapeutic Activity ◽

Human Lung Tumor ◽

Lung Tumor Cell

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Salinomycin inhibits epigenetic modulator EZH2 to enhance Death Receptors in Colon Cancer Stem Cells

10.1101/2020.02.03.932269 ◽

2020 ◽

Author(s):

Anup Kumar Singh ◽

Ayushi Verma ◽

Akhilesh Singh ◽

Rakesh Kumar Arya ◽

Shrankhla Maheshwari ◽

...

Keyword(s):

Stem Cells ◽

Colon Cancer ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Critical Role ◽

Death Receptors ◽

Clinical Samples ◽

Human Colon Cancer

AbstractDrug resistance is one of the trademark features of Cancer Stem Cells (CSCs). We and others have recently shown that paucity of functional death receptors (DR4/5) on the cell surface of tumor cells is one of the major reasons for drug resistance, but their involvement in the context of in CSCs is poorly understood. By harnessing CSC specific cytotoxic function of salinomycin, we discovered a critical role of epigenetic modulator EZH2 in regulating the expression of DRs in colon CSCs. Our unbiased proteome profiler array approach followed by ChIP analysis of salinomycin treated cells indicated that the expression of DRs, especially DR4 is epigenetically repressed in colon CSCs. Concurrently, EZH2 knockdown demonstrated increased expression of DR4/DR5, significant reduction of CSC phenotype such as spheroid formation in-vitro and tumorigenic potential in-vivo in colon cancer. TCGA data analysis of human colon cancer clinical samples shows strong inverse correlation between EZH2 and DR4. Taken together, this study provides an insight about epigenetic regulation of DR4 in colon CSCs and advocates that drug resistant colon cancer can be therapeutically targeted by combining TRAIL and small molecule EZH2 inhibitors.

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