NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells

Abstract

Edited by Xiao-Fan Wang 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 Administrationapproved 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 RNA-Seq and bioinformatics analyses, we observed that NOTCH signaling is a deregulated pathway in enzalutamide-resistant cells. NOTCH2 and c-MYC gene 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.

Changes in the Expression of Notch and Hif-1α Signaling Molecules in Prostate Cancer Progression

“…Multiple molecules have participated in the progression of prostate cancer [8][9][10][11][12] . Notch signaling pathway is involved in the occurrence and development of a variety of tumors, and it can regulate a variety of cell processes, including cell differentiation, proliferation, apoptosis and migration [13,14] . When the Notch ligand specifically binds to the receptor, the Notch signaling pathway is subsequently activated, which in turn activates the transcription of the downstream gene Hes family.…”

“…cancer based on clinical sample [7] . The present study aims to explore the expression and clinical significance of Notch and HIF-1α signaling pathway in the progression of prostate cancer.…”

Notch signalling is a potential resistance mechanism of progenitor cells within patient‐derived prostate cultures following ROS‐inducing treatments

“…Therefore, elucidating the mechanisms of resistance to ADT is necessary. Three recent studies have shown that Notch signalling can contribute to resistance to enzalutamide (androgen receptor antagonist) [46] and that Notch inhibition combined with ADT can cause a synergistic therapeutic effect [47,48]. In addition, Notch signalling has also been implicated in docetaxel resistance [49].…”

LINC00957 Acted as Prognostic Marker Was Associated With Fluorouracil Resistance in Human Colorectal Cancer

“…Recently, emerging evidences suggest that Notch signaling pathway is one of the most important signaling pathways in drug-resistant tumor cells (32). The activated Notch signaling contributes to resistance in enzalutamide-resistant prostate cancer cells (33). Inhibition of Notch signaling reverses docetaxel resistance in prostate cancer (34).…”