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<p><a>Prostate cancer is the second leading cause of
cancer death among men in the United States. The androgen receptor (AR)
antagonist enzalutamide is an FDA-approved drug for treatment of patients with
late-stage prostate cancer and is currently under clinical study for
early-stage prostate cancer treatment.</a> After a short positive response period to
enzalutamide, tumors will develop drug resistance. In these studies, we uncovered
that NOTCH signaling and DNA methylation are a deregulated in
enzalutamide-resistant cells. <i>NOTCH2</i>
and<i> c-MYC </i><a>gene
expression<i> </i>positively correlated with
<i>AR </i>expression in samples from
patients with hormone refractory disease in which AR expression levels
correspond to those typically observed in enzalutamide-resistance</a>. The
expression of Notch signaling components was upregulated in
enzalutamide-resistant cells suggesting the activation of the pathway.
Inhibition of this pathway <i>in vitro</i> and <i>in vivo</i> promoted an
increase in the sensitivity to enzalutamide with an impact on AR expression. On
the other hand, DNMT activity and DNMT3B expression were upregulated in
resistant lines. Enzalutamide induced the expression of DNMT3A and DNMT3B in
prostate cancer cells with a potential role for p53 and pRB in this process.
The overexpression of DNMT3B3, a DNMT3B variant, promoted an
enzalutamide-resistant phenotype in C4-2 cells. DNA methylation inhibition,
using low-concentration decitabine, and <i>DNMT3B</i> knockdown induced a
re-sensitization of resistant prostate cancer cells and tumors to enzalutamide.
Decitabine treatment in enzalutamide-resistant induced a decrease in the expression
of AR-V7 and changes in genes from the apoptosis, DNA repair and mRNA splicing
pathways. Decitabine plus enzalutamide treatment of 22RV1 xenografts induced a
decrease in tumor weight, KI-67 and AR-V7 expression and an increase in
Cleaved-Caspase3 levels. All the above suggest that Notch signaling and DNA
methylation pathways are deregulated after enzalutamide resistance onset, and
targeting these pathways restores the sensitivity to enzalutamide.<b><u></u></b></p>

  1. 10.25394/pgs.13041755.v1
Date16 December 2020
CreatorsElia G Farah (9452786)
Source SetsPurdue University
Detected LanguageEnglish
TypeText, Thesis
RightsCC BY 4.0

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