The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

Fan, Lingling; Peng, Guihong; Hussain, Arif; Fazli, Ladan; Guns, Emma S. Tomlinson; Gleave, Martin; Qi, Jianfei

doi:10.1074/jbc.m115.662155

Cited by 31 publications

(20 citation statements)

References 54 publications

(57 reference statements)

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“…The PGF 2α and 11β-PGF 2α can inactivate proliferator peroxisome activator receptor gamma (PPARγ) and displays anti-proliferative effects (37). Recently, the AKR1C3 has been found to directly interact with E3 ubiquitin ligase siah2 and control its stabilization, and thus regulate the siah2 dependent AR signaling (38). Furthermore, AKR1C3 has been found to specifically interact with the AR and is recruited to the ARE on the promoter of androgen responsive genes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer

Liu

Armstrong

Lou

et al. 2017

Molecular Cancer Therapeutics

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Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a critical mechanism driving resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. We found that overexpression of AKR1C3 confers resistance to abiraterone while downregulation of AKR1C3 re-sensitizes resistant cells to abiraterone treatment. In abiraterone resistant prostate cancer cells, AKR1C3 is overexpressed and the levels of intracrine androgens are elevated. In addition, AKR1C3 activation increases intracrine androgen synthesis and enhances androgen receptor (AR) signaling via activating AR transcriptional activity. Treatment of abiraterone resistant cells with indomethacin, an AKR1C3 inhibitor, overcomes resistance and enhances abiraterone therapy both in vitro and in vivo by reducing the levels of intracrine androgens and diminishing AR transcriptional activity. These results demonstrate that AKR1C3 activation is a critical mechanism of resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. Furthermore, this study provides a preclinical proof-of-principle for clinical trials investigating the combination of targeting AKR1C3 using indomethacin with abiraterone for advanced prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer

Liu

Armstrong

Lou

et al. 2017

Molecular Cancer Therapeutics

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“…For example, AKR1C3 has recently been identified as an AR coactivators and thus may play dual roles in promoting ligand synthesis and AR activation [83]. AKR1C3 has also been shown to bind and stabilize the ubiquitin ligase Siah2, inhibiting its degradation and thereby enhancing Siah2-dependent regulation of AR activity in PCa cells [84]. Notably, AKR1C3 may play a role in modulating epigenetic susceptibility in PCa cells independently of an effect on AR.…”

Section: A Non-classical Role For Dht Metabolizing Enzymesmentioning

confidence: 99%

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

Zhang

Plymate

et al. 2016

HORM CANC

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Androgens play an important role in prostate cancer (PCa) development and progression. Accordingly, androgen deprivation therapy remains the front-line treatment for locally recurrent or advanced PCa, but patients eventually relapse with the lethal form of the disease termed castration resistant PCa (CRPC). Importantly, castration does not eliminate androgens from the prostate tumor microenvironment which is characterized by elevated tissue androgens that are well within the range capable of activating the androgen receptor (AR). In this mini-review, we discuss emerging data that suggest a role for the enzymes mediating pre-receptor control of dihydrotestosterone (DHT) metabolism, including AKR1C2, HSD17B6, HSD17B10 and the UGT family members UGT2B15 and UGT2B17, in controlling intra-tumoral androgen levels, and thereby influencing PCa progression. We review the expression of steroidogenic enzymes involved in this pathway in primary PCa and CRPC, the activity and regulation of these enzymes in PCa experimental models, and the impact of genetic variation in genes mediating pre-receptor DHT metabolism on PCa risk. Finally, we discuss recent data that suggests several of these enzymes may also play an unrecognized role in CRPC progression separate from their role in androgen inactivation.

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“…Recent evidence highlights the importance of non-canonical functions of reductase because the inhibition of enzymatic activities of AKR1Cs fail to kill cancer cells efficiently 15 ; and, some of the family members, such as AKR1C3, exhibit a catalytic-independent ability to bind and stabilize E3 ligase Siah2 by blocking its self-ubiquitination and degradation 23 , which may ultimately promote tumor progression 24 , 25 . In this context, it is intriguing to ask whether and how AKR1C1 functions as a pro-metastatic factor in NSCLC cells in a non-canonical manner.…”

Section: Introductionmentioning

confidence: 99%

AKR1C1 Activates STAT3 to Promote the Metastasis of Non-Small Cell Lung Cancer

Zhu¹,

Ll²,

Fj³

et al. 2018

Theranostics

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Metastasis is the leading cause of mortality for human non-small cell lung cancer (NSCLC). However, it is difficult to target tumor metastasis because the molecular mechanisms underlying NSCLC invasion and migration remain unclear. Methods: GEO data analyses and IHC analyses were performed to identify that the expression level of AKR1C1, a member of human aldo-keto reductase family, was highly elevated in patients with metastasis or metastatic foci of NSCLC patients. Functional analyses (in vitro and in vivo) and quantitative genomic analyses were preformed to confirm the pro-metastatic effects of AKR1C1 and the underlying mechanisms. The correlation of AKR1C1 with the prognosis of NSCLC patients was evaluated using Kaplan-Meier analyses. Results: in NSCLC patients, AKR1C1 expression was closely correlated with the metastatic potential of tumors. AKR1C1 overexpression in nonmetastatic cancer cells significantly promoted metastasis both in vitro and in vivo, whereas depletion of AKR1C1 in highly metastatic tumors potently alleviated these effects. Quantitative genomic and functional analyses revealed that AKR1C1 directly interacted with STAT3 and facilitated its phosphorylation—thus reinforcing the binding of STAT3 to the promoter regions of target genes—and then transactivated these genes, which ultimately promoted tumor metastasis. Further studies showed that AKR1C1 might facilitate the interaction of STAT3 with its upstream kinase JAK2. Intriguingly, AKR1C1 exerted these pro-metastatic effects in a catalytic-independent manner. In addition, a significant correlation between AKR1C1 and STAT3 pathway was observed in the metastatic foci of NSCLC patients, and the AKR1C1-STAT3 levels were highly correlated with a poor prognosis in NSCLC patients. Conclusions: taken together, we show that AKR1C1 is a potent inducer of NSCLC metastasis. Our study uncovers the active function of AKR1C1 as a key component of the STAT3 pathway, which promotes lung cancer metastasis, and highlights a candidate therapeutic target to potentially improve the survival of NSCLC patients with metastatic disease.

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The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

Cited by 31 publications

References 54 publications

Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer

Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer

Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

AKR1C1 Activates STAT3 to Promote the Metastasis of Non-Small Cell Lung Cancer

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