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.
Highlights
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related deaths of men in WesternSiddharth Gupta, Thanakorn Pungsrinont and Ondrej Ženata contributed to this work.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Mechanistically, we have previously shown that androgen receptor (AR) antagonists such as the nonsteroidal atraric acid [5] and compound C28 [6, 7] induce cellular senescence in PCa cells
To analyze whether IL-23 interferes with AR-mediated gene regulation, the expression of endogenous AR target genes KLK3 encoding PSA and FKBP5 were analyzed by room temperature (RT)-qPCR using both LNCaP and C4-2 cells in the presence or absence of the AR antagonists and IL-23
or darolutamide (ODM) represses more potently KLK3 mRNA levels compared with ENZ, whereas FKBP5 is repressed to a similar level
Summary
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related deaths of men in Western. We have previously shown that AR antagonists such as the nonsteroidal atraric acid [5] and compound C28 [6, 7] induce cellular senescence in PCa cells. HORM CANC (2020) 11:182–190 senescent cells are arrested irreversibly in cell cycle and suggested that this pathway is a tumor-suppressive pathway [8, 9]. In addition to intrinsic adaptive signaling of PCa cells, external factors may influence castration resistance. IL23 produced by myeloid-derived suppressor cells (MDSCs) was shown to serve as promoter of CRPC [10]. IL-23 activates the AR signaling and enhances cell proliferation in a non-cell autonomous manner in PCa cells [10]
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