Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Calcagno, Anna Maria; Fostel, Jennifer; To, Kenneth K.W.; Salcido, Crystal D.; Martin, Scott E.; Chewning, Katherine J; Wu, Chung-Pu; Varticovski, Lyuba; Bates, Susan E.; Caplen, Natasha J.; Ambudkar, Suresh V.

doi:10.1038/sj.bjc.6604334

Cited by 115 publications

(90 citation statements)

References 34 publications

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“…16 Similarly, Calcango et al reported that exposure of breast, ovarian and colon cancer cells to low concentrations of doxorubicin for 10 days resulted in development of resistance that was associated with down-regulation of HDAC1. 17 MicroRNAs have been reported previously to induce chemo resistance of cancer cells by different mechanisms such as modulation of intracellular drug concentrations, modulation of drug target, enhancement of drug metabolism, inhibition of apoptosis, regulation of angiogenesis and generation of tumor stem cells. [18][19][20][21][22][23] Among the 14 miRNAs dysregulated in the present study in A549DOX11 cells, 4 (has-miR-1973, 494, 4286 and 29b-3p) have shown the highest level of upregulation (2.99 -4.44 folds) compared with the A549 parental cells.…”

Section: Discussionmentioning

confidence: 99%

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

El‐Awady

Hersi

Al-Tunaiji

et al. 2015

Cancer Biology & Therapy

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Abbreviations: 5AZA, 5-aza-2 0 -deoxycytidine; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; DNMT, DNA methyltransferase; HAT, histone acetyl transferase; HDAC, histone deacetylase; NSCLC, non-small cell lung cancer; PBS, phosphate-buffered saline; SCLC, small-cell lung cancer; TSA, trichostatin A; 5mc, 5-methyl cytosine.Lung cancer cells show inherent and acquired resistance to chemotherapy. The lack of good predictive markers/ novel targets and the incomplete understanding of the mechanisms of resistance limit the success of lung cancer response to chemotherapy. In the present study, we used an isogenic pair of lung adenocarcinoma cell lines; A549 (wild-type) and A549DOX11 (doxorubicin resistant) to study the role of epigenetics and miRNA in resistance/response of non-small cell lung cancer (NSCLC) cells to doxorubicin. Our results demonstrate differential expression of epigenetic markers whereby the level of HDACs 1, 2, 3 and4, DNA methyltransferase, acetylated H2B and acetylated H3 were lower in A549DOX11 compared to A549 cells. Fourteen miRNAs were dys-regulated in A549DOX11 cells compared to A549 cells, of these 14 miRNAs, 4 (has-mir-1973, 494, 4286 and 29b-3p) have shown 2.99 -4.44 fold increase in their expression. This was associated with reduced apoptosis and higher resistance of A549DOX11cells to doxorubicin and etoposide. Sequential treatment with the epigenetic modifiers trichostatin A or 5-aza-2'-deoxycytidine followed by doxorubicin resulted in: (i) enhanced sensitivity of both cell lines to doxorubicin especially at low concentrations, (ii) enhanced doxorubicin-induced DNA damage in both cell lines, (iii) dysregulation of some miRNAs in A549 cells. In conclusion, A549DOX11 cells resistant to DNA damaging drugs have epigenetic profile and miRNA expression different from the sensitive cells. Moreover, epigenetic modifiers may reverse the resistance of certain NSCLC cells to DNA damaging agents by enhancing induction of DNA damage. This may open the door for using epigenetic profile/miRNA expression of some cancer cells as resistance markers/targets to improve response of resistant cells to doxorubicin and for the use of combination doxorubicin/epigenetic modifiers to reduce doxorubicin toxicity.

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Section: Discussionmentioning

confidence: 99%

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

El‐Awady

Hersi

Al-Tunaiji

et al. 2015

Cancer Biology & Therapy

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“…DNA methylation occurs predominantly at CpG sites in the mammalian genome by the DNA methyltransferase (DNMT) enzymes. The majority of CpG pairs are chemically modified by the covalent attachment of a methyl group to the C 5 position of the cytosine ring (Tate & Bird, 1993;Calcagno et al, 2008). Methylation of DNA is regarded as a means of regulating gene expression through two general mechanisms.…”

Section: Epigenetic Regulationmentioning

confidence: 99%

Genetic and Epigenetic Factors Affecting Cytochrome P450 Phenotype and Their Clinical Relevance

Tamási¹,

Falus²

2012

Topics on Drug Metabolism

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“…Our findings suggest that this chemosensitization could depend on down-regulation of ABCG2, which was strongly down-regulated after SOX2 silencing. Indeed, both chemotherapeutic agents are ABCG2 substrates (30,31), and Zheng and co-workers (32) showed that ABCG2 has a major responsibility for side population (stem cell-like subpopulation) resistance to doxorubicin in ATC treatment. Hence, our data strongly support a hierarchical model in which SOX2 plays a central role.…”

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confidence: 99%

Multiple Pluripotent Stem Cell Markers in Human Anaplastic Thyroid Cancer: The Putative Upstream Role of SOX2

Carina

Zito

Pizzolanti

et al. 2013

Thyroid

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Background: Anaplastic thyroid carcinoma (ATC) is a rare and aggressive endocrine tumor with highly undifferentiated morphology. It has been suggested that cancer stem cells (CSCs) might play a central role in ATC. The objectives of this study were (i) to characterize CSCs from ex vivo ATC specimens by investigating the expression of several pluripotent stem cell markers, and (ii) to evaluate in vitro drug resistance modifications after specific CSC transcription factor switch-off. Methods: In ex vivo experiments, eight formalin-fixed, paraffin-embedded ATC specimens were analyzed by reverse-transcription and real-time quantitative PCR and immunohistochemistry. In in vitro experiments using ATC SW1736 cells, the expression levels of OCT-4, NANOG, and ABCG2 and the sensitivity to either cisplatin or doxorubicin were evaluated after silencing. Results: OCT-4, KLF4, and SOX2 transcription factors and C-KIT and THY-1 stem surface antigens showed variable up-regulation in all ATC cases. The SW1736 cell line was characterized by a high percentage of stem population (10.4 -2.1% of cells were aldehyde dehydrogenase positive) and high expression of several CSC markers (SOX2, OCT4, NANOG, C-MYC, and SSEA4). SOX2 silencing down-regulated OCT-4, NANOG, and ABCG2. SOX2 silencing sensitized SW1736 cells, causing a significant cell death increase (1.8-fold) in comparison to control cells with 10 lM cisplatin (93.9 -3.4% vs. 52.6 -9.4%, p < 0.01) and 2.7 fold with 0.5 lM doxorubicin (45.8 -9.9% vs. 17.1 -3.4% p < 0.01). ABCG2 silencing caused increased cell death with both cisplatin (74.9 -1.4%) and doxorubicin treatment (74.1 -0.1%) vs. no-target-treated cells (respectively, 45.8 -1.0% and 48.6 -1.0%, p < 0.001). Conclusions: The characterization of CSCs in ATC through the analysis of multiple pluripotent stem cell markers might be useful in identifying cells with a stem-like phenotype capable of resisting conventional chemotherapy. In addition, our data demonstrate that SOX2 switch-off through ABCG2 transporter down-regulation has a major role in overcoming CSC chemotherapy resistance.

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Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Cited by 115 publications

References 34 publications

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

Genetic and Epigenetic Factors Affecting Cytochrome P450 Phenotype and Their Clinical Relevance

Multiple Pluripotent Stem Cell Markers in Human Anaplastic Thyroid Cancer: The Putative Upstream Role of SOX2

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