Inhibition of the Wnt/β-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer

Zhang, Zhuangzhuang; Cheng, Lijun; Li, Jie; Farah, Elia; Atallah, Nadia M.; Pascuzzi, Pete E.; Gupta, Sanjay; Liu, Xiaoqi

doi:10.1158/0008-5472.can-17-3006

Cited by 130 publications

(101 citation statements)

References 37 publications

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“…Whereas LNCaP and C4-2 are enzalutamide-sensitive PCa cells, MR49F and C4-2R cells are enzalutamide resistant but are derived from LNCaP and C4-2, respectively. Upon comparing the RNA profiles of drug-resistant cell lines to their drug-sensitive counterparts, 1268 genes were identified as differentially expressed genes (DEGs) in C4-2R and 903 genes were found as DEGs in MR49F (Supplementary Tables S1A and S1B), which is in agreement with our published results in C4-2R (20). Using KEGG predefined pathway analysis, pathways related to PCa progression were significantly enriched in C4-2R and MR49F ( Fig.…”

Section: Upregulation Of Ar Correlates With An Active State Of Ephb4supporting

confidence: 87%

“…Nevertheless, how c-Myc is overexpressed in advanced PCa is not well studied. Our previous publications showed the contribution of β-catenin and PI3K/AKT/mTOR to ADT resistance (20,35). Considering that these two pathways are known to elevate c-Myc (36,37), and EphB4 acts upstream of β-catenin and PI3K/AKT/mTOR (7-9), it is reasonable to extrapolate that EphB4 and c-Myc work as the pivot to control the expression of AR through multiple signaling pathways in enzalutamide-resistant CRPC.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance

Lanman

Kong

et al. 2020

Journal of Biological Chemistry

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Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

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Section: Upregulation Of Ar Correlates With An Active State Of Ephb4supporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance

Lanman

Kong

et al. 2020

Journal of Biological Chemistry

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“…Moreover, recent studies have shown that the aberrant activation of the EMT and Wnt/β-catenin pathway also contributes to enzalutamide resistance in prostate cancer ( 105 – 107 ).…”

Section: Mechanisms Of Resistance To Ar Antagonistsmentioning

confidence: 99%

Androgen Receptor in Breast Cancer: From Bench to Bedside

Chen

Yang

et al. 2020

Front. Endocrinol.

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Breast cancer (BC) is one of the most common malignancies and the leading cause of cancer-related mortality in women. Androgen receptor (AR) is frequently expressed in diverse BC subtypes. Accumulating evidence has revealed that AR might be a predictive or prognostic factor and a drug target in BC. AR expression and AR pathways differ in various BC subtypes, thereby resulting in controversial inferences on the predictive and prognostic value of AR. Herein, we summarized the roles of AR in different BC subtypes and AR-targeting therapies based on preclinical and clinical studies. Moreover, we highlighted the possible efficacy of a combination therapy via exploiting the AR-related mechanisms and the research on therapeutic resistance.

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“…However, how JWXLD alleviates inflammation is still not clear. [42,43]. For clinical application purpose, what are the effects of JWXLD on antitumor efficacy of CPT-11 need be explored more in future.…”

Section: Discussionmentioning

confidence: 99%

Jiawei Xianglian Decoction (JWXLD), a Traditional Chinese Medicine (TCM), Alleviates CPT‐11‐Induced Diarrhea in Mice

Lin

Huang

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Irinotecan (CPT-11) is used for therapy of various cancers. However, it has several serious adverse reactions such as diarrhea which is caused by SN-38, the active form of CPT-11. This study aimed to evaluate the effectiveness of Jiawei xianglian decoction (JWXLD), which has been widely used for the treatment of diarrhea in China. In this study, a mouse model with delayed diarrhea was generated by CPT-11. Real-time PCR and enzyme-linked immunosorbent assay (ELISA) were performed to explore intestinal microflora and inflammatory cytokine. Hematoxylin and eosin (H&E) staining was used to analyze tissue morphology. We found that 0.12, 0.23, and 0.46 g JWXLD significantly reduced the severity of CPT-11-induced diarrhea. The levels of Lactobacillus (Lacto) and Bifidobacterium (Bifid) were significantly downregulated by CPT-11, and these effects can be reversed by JWXLD treatment. Furthermore, JWXLD was observed to decrease the activity of β-glucuronidase (β-GD). Histopathological data showed that CPT-11 induced severe intestinal mucosal injury, which was characterized as grade 6, and JWXLD significantly alleviated the injury. In addition, CPT-11 increased the productions of tumor necrosis factor-alpha (TNF-α), tumor necrosis factor-beta (TNF-β), interleukin-6 (IL-6), and interleukin-1 (IL-1), but decreased interleukin-15 (IL-15), interleukin-7 (IL-7), and uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1). In conclusion, JWXLD can counteract these effects caused by CPT-11 treatment. JWXLD could alleviate CPT-11-induced diarrhea.

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Inhibition of the Wnt/β-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer

Cited by 130 publications

References 37 publications

Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance

Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance

Androgen Receptor in Breast Cancer: From Bench to Bedside

Jiawei Xianglian Decoction (JWXLD), a Traditional Chinese Medicine (TCM), Alleviates CPT‐11‐Induced Diarrhea in Mice

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