Anti‐androgen enzalutamide enhances prostate cancer neuroendocrine (NE) differentiation <i>via</i> altering the infiltrated mast cells → androgen receptor (AR) → miRNA32 signals

Dang, Qiang; Li, Lei; Xie, Hongjun; He, Dalin; Chen, Jiaqi; Song, Wenbing; Chang, Luke S.; Chang, Hong-Chiang; Yeh, Shuyuan; Chang, Chawnshang

doi:10.1016/j.molonc.2015.02.010

Cited by 53 publications

(50 citation statements)

References 46 publications

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“…With the clinical implication of novel AR targeted therapies, the question remains unclear if AA and enzalutamide significantly promote NED. Experimental finding has supported the view that the anti‐androgen enzalutamide can promote NED . Previous research has claimed that CRPC patients after first‐line treatment with AA are not at a higher risk for developing NED .…”

Section: Introductionmentioning

confidence: 62%

Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy‐naive metastatic castration‐resistant prostate cancer

et al. 2017

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Section: Introductionmentioning

confidence: 62%

Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy‐naive metastatic castration‐resistant prostate cancer

et al. 2017

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“…(37, 38, 41). Specifically, enzalutamide treatment has been associated with the dysregulated transcription factors and genetic abnormalities that lead to NED (42-44). A third class of mechanism of enzalutamide resistance is AR point mutation.…”

Section: Discussionmentioning

confidence: 99%

TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

Lee

Kim

Kwon

et al. 2019

Preprint

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26In treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-27 generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical 28 benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To 29 determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and 30 found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP 31 human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies 32 demonstrated that TCF4, a transcription factor implicated in Wnt signaling, mediated 33 neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in 34 the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide 35 resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance 36 in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially 37 reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of 38 metastatic CaP were examined, a positive correlation was found between the expression levels of 39 TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide 40 resistance via NED in CaP. 42 Prostate cancer (CaP) is the most common non-cutaneous cancer diagnosed among men and the 43 second leading cause of male cancer deaths in the United States (1). In 2017, it is estimated that 44 26,730 men died from CaP. Although radiation and surgery are quite effective for localized disease, 45 approximately 30% eventually recur following a definitive therapy. More importantly, there is no 46 effective cure for men who present with metastatic CaP as the 5-year relative survival rate is only 47 29% (1). In patients with a metastatic disease, medical or surgical castration is generally the 48 accepted first-line therapy. Yet, castration-resistant prostate cancer (CRPC) eventually emerges 49 with a median time of 18-24 months (2, 3). Once CRPC develops, secondary hormonal 50 manipulation, immunotherapy, and chemotherapy are marginally effective and the average life 51 expectancy is ~5 years (4, 5). 52Enzalutamide is a FDA-approved second-generation androgen receptor (AR) antagonist 53 that blocks ligand binding, nuclear translocation, DNA binding, and coactivator recruitment of 54 ARs (6). In multiple clinical trials, enzalutamide has been shown to prolong overall and 55 progression-free survival, improve patient-reported quality of life, and delay the development of 56 skeletal-related complications in men with metastatic CRPC who are chemotherapy naïve or have 57 previously received docetaxel (7-9). However, despite the significant initial therapeutic benefits 58 of enzalutamide, resistance inevitably occurs with a median time of 4.8 months. Although the 59 precise mechanistic details underlying the emergence of enzalutamide resistance is largely 60 ...

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“…As normal prostatic NE cells do not divide, there is strong evidence suggesting that transdifferentiation from prostate epithelial cells is the source of these NEPC cells. And this transdifferentiation can be influenced by a variety of means such as androgen ablation (43), hypoxia (44) and a particular tumor microenvironment (TME) (45). …”

Section: Discussionmentioning

confidence: 99%

Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemoresistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

Chen

Sun

et al. 2016

Oncogene

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Prostatic neuroendocrine cells (NE) are an integral part of prostate cancer (PCa) that are associated with PCa progression. As the current androgen-deprivation therapy (ADT) with anti-androgens may promote the neuroendocrine PCa (NEPCa) development, and few therapies can effectively suppress NEPCa, understanding the impact of NEPCa on PCa progression may help us to develop better therapies to battle PCa. Here we found NEPCa cells could increase the docetaxel-resistance of their neighboring PCa cells. Mechanism dissection revealed that through secretion of PTHrP, NEPCa cells could alter the p38/MAPK/Hsp27 signals in their neighboring PCa cells that resulted in increased androgen receptor (AR) activity via promoting AR nuclear translocation. The consequences of increased AR function might then increase docetaxel-resistance via increasing p21 expression. In vivo xenograft mice experiments also confirmed NEPCa could increase the docetaxel-resistance of neighboring PCa, and targeting this newly identified PTHrP/p38/Hsp27/AR/p21 signaling pathway with either p38 inhibitor (SB203580) or sh-PTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa.

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Anti‐androgen enzalutamide enhances prostate cancer neuroendocrine (NE) differentiation via altering the infiltrated mast cells → androgen receptor (AR) → miRNA32 signals

Cited by 53 publications

References 46 publications

Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy‐naive metastatic castration‐resistant prostate cancer

Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy‐naive metastatic castration‐resistant prostate cancer

TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemoresistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

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