Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer

Androgen deprivation therapy (ADT) is standard-of-care for advanced-stage prostate cancer, and enzalutamide (Xtandi®, Astellas, Northbrook, IL, USA), a second generation antiandrogen, is prescribed in this clinical setting. The response to this medication is usually temporary with the rapid emergence of drug resistance. A better understanding of gene expression changes associated with enzalutamide resistance will facilitate circumventing this problem. We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-2B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation. Next-Gen sequencing detected 9409 and 7757 genes differentially expressed in LNCaP and C4-2B cells, compared to their parental counterparts. A subset of differentially expressed genes were validated by qRT-PCR. Analysis by the i-pathway revealed membrane transporters including solute carrier proteins, ATP-binding cassette transporters, and drug metabolizing enzymes as the most prominent genes dysregulated in resistant cell lines. RNA-Seq data demonstrated predominance of solute carrier genes SLC12A5, SLC25A17, and SLC27A6 during metabolic reprogramming and development of drug resistance. Upregulation of these genes were associated with higher uptake of lactic/citric acid and lower glucose intake in resistant cells. Our data suggest the predominance of solute carrier genes during metabolic reprogramming of prostate cancer cells in an androgen-deprived environment, thus signifying them as potentially attractive therapeutic targets.

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The association of Id-1, MIF and GSTpi with acquired drug resistance in hormone independent prostate cancer cells

Oncology Reports ◽

10.3892/or.13.5.983 ◽

2005 ◽

Author(s):

Jau-Chen Lin ◽

Sun-Yran Chang ◽

Dar-Shih Hsieh ◽

Chi-Feng Lee ◽

Dah-Shyong Yu

Keyword(s):

Prostate Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Prostate Cancer Cells ◽

Acquired Drug Resistance

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Mutual Expression of ALDH1A1, LOX, and Collagens in Ovarian Cancer Cell Lines as Combined CSCs- and ECM-Related Models of Drug Resistance Development

International Journal of Molecular Sciences ◽

10.3390/ijms20010054 ◽

2018 ◽

Vol 20 (1) ◽

pp. 54 ◽

Cited By ~ 9

Author(s):

Karolina Sterzyńska ◽

Andrzej Klejewski ◽

Karolina Wojtowicz ◽

Monika Świerczewska ◽

Marta Nowacka ◽

...

Keyword(s):

Ovarian Cancer ◽

Extracellular Matrix ◽

Drug Resistance ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Lysyl Oxidase ◽

Resistant Cell ◽

Pcr Analysis ◽

Ovarian Cancer Cells

A major contributor leading to treatment failure of ovarian cancer patients is the drug resistance of cancer cell. CSCs- (cancer stem cells) and ECM (extracellular matrix)-related models of drug resistance are described as independently occurring in cancer cells. Lysyl oxidase (LOX) is another extracellular protein involved in collagen cross-linking and remodeling of extracellular matrix and has been correlated with tumor progression. The expression of LOX, COL1A2, COL3A1, and ALDH1A1 was performed in sensitive (A2780, W1) and resistant to paclitaxel (PAC) (A2780PR1 and W1PR2) and topotecan (TOP) (W1TR) cell lines at the mRNA (real-time PCR analysis) and protein level (Western blot and immunofluorescence analysis). The ALDH1A1 activity was measured with the ALDEFLUOR test and flow cytometry analysis. The protein expression in ovarian cancer tissues was determined by immunohistochemistry. We observed an increased expression of LOX and collagens in PAC and TOP resistant cell lines. Subpopulations of ALDH1A1 positive and negative cells were also noted for examined cell lines. Additionally, the coexpression of LOX with ALDH1A1 and COL1A2 with ALDH1A1 was observed. The expression of LOX, collagens, and ALDH1A1 was also detected in ovarian cancer lesions. In our study LOX, ALDH1A1 and collagens were found to be coordinately expressed by cells resistant to PAC (LOX, ALDH1A1, and COL1A2) or to TOP (LOX and ALDH1A1). This represents the study where molecules related with CSCs (ALDH1A1) and ECM (LOX, collagens) models of drug resistance are described as occurring simultaneously in ovarian cancer cells treated with PAC and TOP.

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Abstract 1722: The outer nuclear membrane population of Bcl-2 contributes to drug resistance in human prostate cancer cells.

10.1158/1538-7445.am2013-1722 ◽

2013 ◽

Author(s):

Theodore E. Ewachiw ◽

Jennifer R. Cohen ◽

Simon A. Williams

Keyword(s):

Prostate Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Nuclear Membrane ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Outer Nuclear Membrane

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Abstract 1467: Metabolic reprogramming fuels prostate cancer cells towards enzalutamide resistance

10.1158/1538-7445.am2020-1467 ◽

2020 ◽

Author(s):

Shiv S. Verma ◽

Eswar Shankar ◽

Rajnee Kanwal ◽

Ricky Chan ◽

Sanjay Gupta

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Metabolic Reprogramming ◽

Prostate Cancer Cells

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Acidosis induces multi-drug resistance in rat prostate cancer cells (AT1)in vitroandin vivoby increasing the activity of the p-glycoproteinviaactivation of p38

International Journal of Cancer ◽

10.1002/ijc.23818 ◽

2008 ◽

Vol 123 (11) ◽

pp. 2532-2542 ◽

Cited By ~ 66

Author(s):

Christoph Sauvant ◽

Martin Nowak ◽

Claudia Wirth ◽

Bettina Schneider ◽

Anne Riemann ◽

...

Keyword(s):

Prostate Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Multi Drug Resistance ◽

Prostate Cancer Cells ◽

Rat Prostate

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Docetaxel-ST1481 sequence exerts a potent cytotoxic activity on hormone-resistant prostate cancer cells by reducing drug resistance-related gene expression

The Prostate ◽

10.1002/pros.21055 ◽

2009 ◽

Vol 70 (2) ◽

pp. 219-227 ◽

Cited By ~ 3

Author(s):

Francesco Fabbri ◽

Giovanni Brigliadori ◽

Silvia Carloni ◽

Paola Ulivi ◽

Anna Tesei ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Drug Resistance ◽

Cytotoxic Activity ◽

Cancer Cells ◽

Related Gene ◽

Prostate Cancer Cells ◽

Hormone Resistant Prostate Cancer

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Contribution of microRNA-200b-3p to radiation therapy resistance in 22RV1 prostate cancer cells.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.89 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 89-89

Author(s):

John Thoms ◽

Satoko Aoki ◽

Lourdes Pena Castillo

Keyword(s):

Prostate Cancer ◽

Radiation Therapy ◽

Cancer Cells ◽

Cell Lines ◽

Clonogenic Survival ◽

Negative Control ◽

Differentially Expressed ◽

Prostate Cancer Cells ◽

Altered Expression ◽

Resistant Phenotype

89 Background: Radiation therapy (RT) is a standard treatment option for men with localized prostate cancer. Despite having well-established treatment regimens, such men still fail RT at a rate of up to 30-50%. RT resistant phenotype is a key component leading to treatment failure. MicroRNAs (miRNAs) can influence the response to RT, and the abundance or lack of certain miRNAs can induce a RT resistant phenotype through alteration of survival pathways. We show that altered expression of miR-200b-3p plays an important role in contributing to RT resistance. Methods: RT resistant subline from the parental 22RV1 prostate cancer cell line was generated by exposure to fractionated RT – 22RV1-RT. The global expression level of miRNAs and mRNA was determined, using the Affymetrix GeneChip®: miRNA 4.0 and Human Gene 2.0 ST Arrays. Parental and 22RV1-RT cells were transfected with miR-200b-3p mimics or negative control. The influence of miR-200b-3p on cellular proliferation, morphology, migration, clonogenic survival and response to RT was determined by standard assays. Results: MiR-200b-3p was the only miRNA that was statistically differentially expressed between the two cell lines. There were 39 differentially expressed genes. Of the 65 genes predicted to be regulated by miR-200b-3p as identified from miRTarBase, only Fibronectin 1 (FN1) was in common. FN1 was up-regulated in 22RV1- RT cells. MiR-200b-3p mimics; in comparison to negative control mimics, suppressed cell proliferation in both cell lines. Both cell lines with negative control mimics have fibroblastic-type morphology and display a stretched shape following RT. While, cells transfected with miR-200b-3p mimics demonstrated a round morphology and formed clusters following RT. Over-expression of miR-200b-3p mimics inhibited cell migration synergically with RT and demonstrated a lower degree of clonogenic survival following RT in 22RV1-RT cells compared to negative control mimics. Surprisingly, miR-200b-3p mimics reversed the observed RT resistance and the sensitivity to RT was to the same degree as the parental 22RV1 cells. Conclusions: Together, these data suggest that miR-200b-3p independently contributes to RT resistance in 22RV1 prostate cancer cells.

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