MicroRNA expressions associated with progression of prostate cancer cells to antiandrogen therapy resistance

    Authors

    R. Ottman; C. Nguyen; R. Lorch;R. Chakrabarti

    Comments

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    Abbreviated Journal Title

    Mol. Cancer

    Keywords

    MicroRNA; Prostate cancer; Antiandrogen; Androgen deprivation; Drug; resistance; Expression profiling; NF-KAPPA-B; ACUTE MYELOID-LEUKEMIA; GROWTH-FACTOR RECEPTOR; HUMAN; CERVICAL-CANCER; ANDROGEN RECEPTOR; BREAST-CANCER; TUMOR-SUPPRESSOR; GASTRIC-CANCER; HEPATOCELLULAR-CARCINOMA; TRANSCRIPTIONAL ACTIVITY; Biochemistry & Molecular Biology; Oncology

    Abstract

    Background: Development of resistance to androgen deprivation therapy (ADT) is a major obstacle for the management of advanced prostate cancer. Therapies with androgen receptor (AR) antagonists and androgen withdrawal initially regress tumors but development of compensatory mechanisms including AR bypass signaling leads to re-growth of tumors. MicroRNAs (miRNAs) are small regulatory RNAs that are involved in maintenance of cell homeostasis but are often altered in tumor cells. Results: In this study, we determined the association of genome wide miRNA expression (1113 unique miRNAs) with development of resistance to ADT. We used androgen sensitive prostate cancer cells that progressed to ADT and AR antagonist Casodex (CDX) resistance upon androgen withdrawal and treatment with CDX. Validation of expression of a subset of 100 miRNAs led to identification of 43 miRNAs that are significantly altered during progression of cells to treatment resistance. We also show a correlation of altered expression of 10 proteins targeted by some of these miRNAs in these cells. Conclusions: We conclude that dynamic alterations in miRNA expression occur early on during androgen deprivation therapy, and androgen receptor blockade. The cumulative effect of these altered miRNA expression profiles is the temporal modulation of multiple signaling pathways promoting survival and acquisition of resistance. These early events are driving the transition to castration resistance and cannot be studied in already developed CRPC cell lines or tissues. Furthermore our results can be used a prognostic marker of cancers with a potential to be resistant to ADT.

    Journal Title

    Molecular Cancer

    Volume

    13

    Publication Date

    1-1-2014

    Document Type

    Article

    Language

    English

    First Page

    21

    WOS Identifier

    WOS:000331563200001

    ISSN

    1476-4598

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