Abstract
Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a Food and Drug Administration- approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period, tumors will develop drug resistance. In this study using RNASeq and bioinformatics analyses, we observed that NOTCH signaling is a deregulated pathway in enzalutamide-resistant cells. NOTCH2 and c-MYCgene expression positively correlated with AR expression in samples from patient with hormone refractory disease in which AR expression levels correspond to those typically observed in enzalutamide resistance. Cleaved NOTCH1, HES1 (Hes family BHLH transcription factor 1), and c-MYC protein expression levels are elevated in two enzalutamide-resistant cell lines, MR49F and C4-2R, indicating NOTCH signaling activation. Moreover, inhibition of the overexpressed ADAM metallopeptidase domain 10 (ADAM10) in the resistant cells induces an exclusive reduction in cleaved NOTCH1 expression. Furthermore, exposure of enzalutamide-resistant cells to both PF-03084014 and enzalutamide increased cell death, decreased colony formation ability, and resensitized cells to enzalutamide. Knockdown of NOTCH1 in C4-2R increased enzalutamide sensitivity by decreasing cell proliferation and increasing cleaved PARP expression. In a 22RV1 xenograft model, PF-03084014 and enzalutamide decreased tumor growth through reducing cell proliferation and increasing apoptosis. These results indicate that NOTCH1 signaling may contribute to enzalutamide resistance in prostate cancer, and inhibition of NOTCH signaling can resensitize resistant cells to enzalutamide.
| Original language | English |
|---|---|
| Pages (from-to) | 8543-8554 |
| Number of pages | 12 |
| Journal | Journal of Biological Chemistry |
| Volume | 294 |
| Issue number | 21 |
| DOIs | |
| State | Published - May 24 2019 |
Bibliographical note
Funding Information:This work was supported by National Institutes of Health Grants R01 CA157429, R01 CA192894, R01 CA196835, and R01 CA196634 (to X. L.). The work was also supported by Purdue University Center for Cancer Research Grant P30 CA023168. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the respon-sibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
This work was supported by National Institutes of Health Grants R01 CA157429, R01 CA192894, R01 CA196835, and R01 CA196634 (to X. L.). The work was also supported by Purdue University Center for Cancer Research Grant P30 CA023168. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2019 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
