Interleukin-23 Represses the Level of Cell Senescence Induced by the Androgen Receptor Antagonists Enzalutamide and Darolutamide in Castration-Resistant Prostate Cancer Cells

Abstract

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related deaths of men in Western countries. Androgen deprivation therapy is initially successful, however eventually fails, and tumors progress to the more aggressive castration-resistant PCa (CRPC). Yet, androgen receptor (AR) usually remains as a major regulator of tumor cell proliferation in CRPC. Interleukin-23 (IL-23) was recently shown to promote the development of CRPC by driving AR transcription. Here we used the androgen-sensitive LNCaP, castration-resistant C4-2, and 22Rv1 cells. Interestingly, cellular senescence is induced in these human cell lines by treatment with the AR antagonists enzalutamide (ENZ) or darolutamide (ODM), which might be one underlying mechanism for inhibition of PCa cell proliferation. Treatment with IL-23 alone did not change cellular senescence levels in these cell lines, whereas IL-23 inhibited significantly cellular senescence levels induced by ENZ or ODM in both CRPC cell lines C4-2 and 22Rv1 but not in LNCaP cells. This indicates a response of IL-23 specific in CRPC cells. Generating LNCaP and C4-2 three-dimensional (3D) spheroids and treatment with AR antagonists resulted in the reduced spheroid volume and thus growth inhibition. However, the combination of AR antagonists with IL-23 did not affect the antagonist-mediated reduction of spheroid volumes. This observation was confirmed with proliferation assays using adherent monolayer cell cultures. Taken together, the data indicate that IL-23 treatment reduces the AR antagonists-induced level of cellular senescence of CRPC cells, which could be one possible mechanism for promoting castration resistance.

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

“…In line with this, Enz decreases cell growth and on one hand was reported to induce apoptosis [79]. On the other hand, induction of cellular senescence in both CSPC LNCaP and the CRPC C4-2 cells upon Enz treatment was also reported [61,62]. Accordingly, the expression of p16 INK4A is induced by Enz in both cell lines.…”

“…Darolutamide treatment results in growth inhibition and cellular senescence induction in both CSPC and CRPC PCa cell lines [62]. Similar to Enz, the induction of cellular senescence is associated with upregulated expression of the senescence regulator p16 INK4A in both LNCaP and C4-2 cells [62].…”

“…It is a full- and high-affinity AR antagonist, which overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs [ 85 , 88 ]. Darolutamide treatment results in growth inhibition and cellular senescence induction in both CSPC and CRPC PCa cell lines [ 62 ]. Similar to Enz, the induction of cellular senescence is associated with upregulated expression of the senescence regulator p16 INK4A in both LNCaP and C4-2 cells [ 62 ].…”

Anti-Proliferative, Anti-Angiogenic and Safety Profiles of Novel HDAC Inhibitors for the Treatment of Metastatic Castration-Resistant Prostate Cancer

“…However, the reason for this may be the fact that the spheroids were grown for 1 day. This is shorter than other 3D spheroid studies, which allow for the growth of spheroids for a minimum of 3 days before treatment [42,44,45]. Therefore, a similar experimental design should be used to compare the clinically approved drugs with Jazz90 and Jazz167 in future studies.…”

Response to Androgens and Androgen Receptor Antagonists in the Presence of Cytokines in Prostate Cancer

“…IL-23 could inhibit the effects of the anti-androgens enzalutamide and darolutamide on induction of cellular senescence. IL-23 was found to activate AR-mediated transcription [12]. High IL-23 levels were measured in sera from patients with advanced prostate cancer.…”