Data from Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46
Yen‐Nien LiuShaoxi NiuWeiyu ChenQingfu ZhangYulei TaoWeihao ChenKuo‐Ching JiangXufeng ChenHuaiyin ShiAijun LiuJinhang LiYanjing LiYi‐Chao LeeXu ZhangJiaoti Huang
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<div>AbstractPurpose:<p>The molecular targets for castration-resistant prostate cancer (CRPC) are unknown because the disease inevitably recurs, and therapeutic approaches for patients with CRPC remain less well understood. We sought to investigate regulatory mechanisms that result in increased therapeutic resistance, which is associated with neuroendocrine differentiation of prostate cancer and linked to dysregulation of the androgen-responsive pathway.</p>Experimental Design:<p>The underlying intracellular mechanism that sustains the oncogenic network involved in neuroendocrine differentiation and therapeutic resistance of prostate cancer was evaluated to investigate and identify effectors. Multiple sets of samples with prostate adenocarcinomas and CRPC were assessed via IHC and other assays.</p>Results:<p>We demonstrated that leukemia inhibitory factor (LIF) was induced by androgen deprivation therapy (ADT) and was upregulated by ZBTB46 in prostate cancer to promote CRPC and neuroendocrine differentiation. LIF was found to be induced in patients with prostate cancer after ADT and was associated with enriched nuclear ZBTB46 staining in high-grade prostate tumors. In prostate cancer cells, high ZBTB46 output was responsible for the activation of LIF-STAT3 signaling and neuroendocrine-like features. The abundance of LIF was mediated by ADT-induced ZBTB46 through a physical interaction with the regulatory sequence of <i>LIF</i>. Analysis of serum from patients showed that cases of higher tumor grade and metastatic prostate cancer exhibited higher LIF titers.</p>Conclusions:<p>Our findings suggest that LIF is a potent serum biomarker for diagnosing advanced prostate cancer and that targeting the ZBTB46–LIF axis may therefore inhibit CRPC development and neuroendocrine differentiation after ADT.</p></div>Keywords:
Neuroendocrine differentiation
The androgen receptor has been purified in the ‘70s and cloned in the ‘80s. It is a member of the steroid receptor superfamily and mediated the most important effects of androgen in androgen dependent or sensitive tissues. Several physiological function of the brain are differentially controlled in the two sexes and androgens play specific role in the processes of sexual differentiation and it is involved in the maintenance of male sex behaviour in adulthood. When mutated, the androgen receptor may impact on many of these androgen-regulated activities because of a loss of androgenic function in target cells. However, in the case of a peculiar type of mutation, the elongation of the polyglutamine tract normally present in its N-terminus, the androgen receptor becomes neurotoxic and induces cells death of a number of motoneurons in the spinal cord, which express very high level of this protein. Here, we will briefly discuss the most important actions of androgen receptor-mediated androgen activity in the brain and the mechanisms by which the mutant androgen receptor may lead to neurodegeneration in Spinal and Bulbar Muscular Atrophy (SBMA).
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Androgen receptors(AR) were found in many tissues. And androgen receptor exert its biological effect by binding with androgen. Androgen receptors were influenced by a lot of substance. Among them, androgen plays an important role in the field. For example, androgen can alter the amount, the metabolism and the structure of AR. The influence of androgen on the androgen receptors is reviewed.
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Androgens secreted by the testes bind the androgen receptor in developing target tissues to induce the expression of genes required for male sexual differentiation and development. Androgen concentration and androgen receptor levels vary in male reproductive target tissues during development. Exposure to environmental androgen antagonists during critical windows of fetal and postnatal development can inhibit male sexual development by blocking transcription of androgen-dependent genes. As the sensitivity to androgen antagonists under conditions of varying androgen concentrations and varying androgen receptor levels is unknown, we used a luciferase reporter assay to investigate the transcriptional effects of a known androgen antagonist (the vinclozolin metabolite M2) at different androgen concentrations and different androgen receptor levels. The ability of M2 to inhibit transcription was greater at lower concentrations of androgen (5α-dihydrotestosterone) and androgen receptor. The data were modeled to determine the dose-response surface of M2 and androgen receptor concentrations at different 5α-dihydrotestosterone levels and the relationship of the 3 components to the response. The model and hypothesis testing results suggest that, at 0.01 and 0.1 nM 5α-dihydrotestosterone concentrations within the expected in vivo range of free androgen levels during development, the response-surface shapes were similar and the interaction of the androgen receptor and M2 concentrations to the response were similarly antagonistic. Thus, two components of the developmental stage, androgen and androgen receptor concentrations, are critical for sensitivity to the inhibitory effects of an androgen antagonist.
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The male hormone androgen is a growth/survival factor for its target tissues or organs. Yet, the underlying mechanism is incompletely understood. Here, we report that androgen via p21 inhibits tumor necrosis factor alpha-induced JNK activation and apoptosis. Inhibition by androgen requires the transcription activity of androgen receptor (AR) and de novo protein synthesis. Androgen.AR induces expression of p21 that in turn inhibits tumor necrosis factor alpha-induced JNK and apoptosis. Furthermore, genetic interruption of p21 alleles abolishes the inhibition by androgen. Our results reveal a novel cross-talk between androgen x AR and JNK, thereby providing a molecular mechanism underlying the survival function of androgen.
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Recent research provides a more detailed understanding of the androgen and androgen receptor system role in mammalian female physiology indicating the essential value in reproduction. Here, we summarize androgen and androgen receptor biochemical and immunohistochemical brain studies of different vertebrate classes and, in detail, our investigations conducted on the female of the seasonal breeders, the amphibian anura Rana esculenta and the reptile, Podarcis sicula. The results have been achieved seasonally through plasma steroid radioimmunoassay and brain androgen binding activity by biochemical identification as well by androgen receptor immunolocalization and neuroanatomical distribution. Taken together, the seasonal fluctuations and the signal intensity in the different target cells of established encephalic district extend knowledge of the central action of the androgen in the lower vertebrate providing considerable understanding of the physiology role of the androgen/androgen receptor system in the female lower vertebrate reproduction.
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We investigated bcl-2 and androgen receptor (AR) expression in an androgen-independent subline derived from mouse androgen-dependent mammary carcinoma cells. The androgen-independent SCAI cells were subcloned by cultivating androgen-dependent SC2G cells in serum-free, androgen-free conditions. The growth of the SCAI cells was not affected by testosterone. Western blot analysis showed greater expression of Bcl-2 protein in SCAI cells than in SC2G cells. A four-day culture with 4 microM antisense oligonucleotide complementary to mouse bcl-2 significantly decreased the viability of SCAI cells, when compared with sense control. The amount of the AR-mRNA expression in SCAI cells was slightly weaker. Direct sequence analysis showed no mutations in the AR of either androgen-dependent or -independent cells. These data indicate that the increased expression of Bcl-2 protein plays an important role in acquiring tolerance for the testosterone ablation, although it is not related to AR gene alteration.
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Although androgens have myriad effects on the skeleton, the regulation of androgen action in bone is not well understood. Androgen receptors (ARs) are known to play an important role in mediating androgen action. We have examined the effects of androgens and other sex steroids on AR levels in osteoblastic cells in vitro using two clonal human cell lines, SaOS-2 and U-2 OS. AR protein levels were quantitated both by specific androgen binding studies and Western analyses, and AR messenger RNA was measured with RNase protection assays. Potential changes in AR functionality was assessed by reporter assays. Treatment of osteoblastic cells with the nonaromatizable androgen 5alpha-dihydrotestosterone (DHT) increased specific androgen binding 2-to 4-fold. Similar increases in AR protein levels were documented by Western analysis in both cell lines. The androgen-mediated increase in receptor levels was time and dose dependent as well as androgen specific. Steady-state AR messenger RNA levels were also increased by DHT. When AR concentrations in osteoblastic cells were elevated with exogenous receptor, there was an enhancement of DHT responsiveness, measured by increased trans-activation of an androgen-responsive promoter. Thus, androgen exposure increased androgen receptor protein levels and specific androgen binding in osteoblastic cells. Androgen action as measured by androgen-mediated transcriptional activation is enhanced in the presence of elevated AR levels. Consequently, these studies have revealed an additional means by which androgens may modulate skeletal metabolism.
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Content of androgen receptor, retention of injected testosterone and karyotype of SC115, androgen-dependent tumor, were compared with those of CS2, an androgen-independent subline derived from SC115. Although Bmax was less than that of SC115, androgen receptor was present in the cytosol and the nuclear extract from CS2. To examine the ability for androgen retention, a large amount of testosterone was injected into tumor-bearing mice, and the amount of androgen in the crude nuclear and postnuclear fractions of tumors was compared. In both fractions, retention of injected androgen was higher in the SC115 than in the CS2. Since most of the injected testosterone was not metabolized in the tissues and the injection of testosterone 5α-reductase inhibitor showed no significant influence on the growth rate of the SC115, intracellular active androgen was assumed to be testosterone in these tumor cells. As the CS2was tetraploid, the androgen independency of the CS2 seems to be related to chromosomal changes.
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