Abstract
Simple SummaryMetastatic castration-resistant prostate cancer is still untreatable, and patients have a very short life expectancy after diagnosis. One factor that makes metastatic castration-resistant prostate cancer so aggressive and difficult to treat is neuroendocrine differentiation of prostate carcinoma cells. We already showed that neuroendocrine differentiation of LNCaP cells results in increased AKT3 expression. The aim of this study was to demonstrate the role of AKT3 in neuroendocrine differentiation. Therefore, the previously obtained in vitro data were validated and extended to tissue from patient with neuroendocrine prostate cancer, where we show the presence of AKT3 in neuroendocrine cells. Furthermore, we demonstrate the oncogenic consequences of an increased AKT3 expression including inactivation of apoptotic proteins and a potential role of some miR-17 family members, negatively regulating AKT3, in neuroendocrine differentiation.Patients with advanced prostate carcinoma are often treated with an androgen deprivation therapy but long-term treatment can result in a metastatic castration-resistant prostate cancer. This is a more aggressive, untreatable tumor recurrence often containing areas of neuroendocrine differentiated prostate cancer cells. Using an in vitro model of NE-like cancer cells, it could previously be shown that neuroendocrine differentiation of LNCaP cells leads to a strong deregulation of mRNA and miRNA expression. We observe elevated RNA and protein levels of AKT Serine/Threonine Kinase 3 (AKT3) in neuroendocrine-like LNCaP cells. We used prostate resections from patients with neuroendocrine prostate cancer to validate these results and detect a co-localization of neuroendocrine marker genes with AKT3. Analysis of downstream target genes FOXO3A and GSK3 strengthens the assumption AKT3 may play a role in neuroendocrine differentiation. Overexpression of AKT3 shows an increased survival rate of LNCaP cells after apoptosis induction, which in turn reflects the significance in vivo or for treatment. Furthermore, miR-17, −20b and −106b, which are decreased in neuroendocrine-like LNCaP cells, negatively regulate AKT3 biosynthesis. Our findings demonstrate AKT3 as a potential therapeutic target and diagnostic tool in advanced neuroendocrine prostate cancer and a new mRNA–miRNA interaction with a potential role in neuroendocrine differentiation of prostate cancer.
Highlights
Prostate carcinoma (PCa) is the second most diagnosed cancer type in men worldwide [1]
Cancers 2021, 13, 578 noma, we validated AKT Serine/Threonine Kinase 3 (AKT3) expression in NE-like LNCaP cells compared to undifferentiated LNCaP cells in four independent differentiations by qRT-PCR (Figure 1A)
The results show a strong accordance to former microarray results and reveal a significant (p = 0.0007) induction of AKT3 (4-fold)
Summary
Prostate carcinoma (PCa) is the second most diagnosed cancer type in men worldwide [1]. The development and progression of PCa is strongly dependent on androgen, making the androgen receptor (AR) one of the most important therapeutic targets in advanced and metastatic PCa. Therapeutic agents focus on the inhibition of androgen production or on blocking AR signaling [2,3]. Many different mechanisms switching from androgen dependent to androgen independent tumor growth are discussed, including enhanced AR expression, AR mutations or AR evasion through other signaling pathways. Another disadvantage of androgen deprivation therapy (ADT) is the induction of neuroendocrine transdifferentiation (NETD) of prostate cancer cells to neuroendocrine (NE)-like tumor cells (NETC) [5]
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