Androgens, lipogenesis and prostate cancer

Swinnen, Johannes V.; Heemers, Hannelore V.; Sande, Tine Van de; Schrijver, Ellen De; Brusselmans, Koen; Heyns, Walter; Verhoeven, Guido

doi:10.1016/j.jsbmb.2004.10.013

Cited by 157 publications

(150 citation statements)

References 52 publications

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“…Androgen-sensitive cells that are deprived of androgen exit the cell cycle and arrest in G0 (Knudsen et al 1998, Agus et al 1999, much like the cell cycle effects of combined 17-AAG and bicalutamide treatment observed here. Finally, lipid metabolism is highly regulated by androgens in prostate cancer cells (Swinnen et al 2004). Bicalutamide inhibits lipid synthesis in LNCaP cells (Swinnen et al 1996), and increased levels of key lipogenic enzymes have been reported in CRPC patients (Rossi et al 2003, Ettinger et al 2004.…”

Section: Discussionmentioning

confidence: 99%

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Centenera¹,

Carter²,

Gillis³

et al. 2015

Endocrine-Related Cancer

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Persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) underpins the urgent need for therapeutic strategies that better target this pathway. Combining classes of agents that target different components of AR signaling has the potential to delay resistance and improve patient outcomes. Many oncoproteins, including the AR, rely on the molecular chaperone heat shock protein 90 (Hsp90) for functional maturation and stability. In this study, enhanced anti-proliferative activity of the Hsp90 inhibitors 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922 in androgen-sensitive and CRPC cells was achieved when the agents were used in combination with AR antagonists bicalutamide or enzalutamide. Moreover, significant caspasedependent cell death was achieved using sub-optimal agent doses that individually have no effect. Expression profiling demonstrated regulation of a broadened set of AR target genes with combined 17-AAG and bicalutamide compared with the respective single agent treatments. This enhanced inhibition of AR signaling was accompanied by impaired chromatin binding and nuclear localization of the AR. Importantly, expression of the AR variant AR-V7 that is implicated in resistance to AR antagonists was not induced by combination treatment. Likewise, the heat shock response that is typically elicited with therapeutic doses of Hsp90 inhibitors, and is a potential mediator of resistance to these agents, was significantly reduced by combination treatment. In summary, the co-targeting strategy in this study more effectively inhibits AR signaling than targeting AR or HSP90 alone and prevents induction of key resistance mechanisms in prostate cancer cells. These findings merit further evaluation of this therapeutic strategy to prevent CRPC growth.

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Section: Discussionmentioning

confidence: 99%

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Centenera¹,

Carter²,

Gillis³

et al. 2015

Endocrine-Related Cancer

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“…49 It has been postulated that deregulation of SREBP controlled gene expression could contribute to cell transformation and tumor development. 50 SREBP bind to DNA sequences that contain a direct repeat of 5 0 -PyCAPy-3 0 , designed as the sterol regulatory element (SRE). SREBP is a known transcriptional activator of PPARg 51 and is a suggested activator of A-FABP.…”

Section: Discussionmentioning

confidence: 99%

A‐FABP, a candidate progression marker of human transitional cell carcinoma of the bladder, is differentially regulated by PPAR in urothelial cancer cells

Boiteux

Lascombe

Roche

et al. 2009

Intl Journal of Cancer

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Superficial pT1 bladder tumors are characterized by a high risk of recurrence and progression in grade and stage. Few studies provided evidence that loss of adipocyte-fatty acid binding protein (A-FABP) expression was associated with bladder cancer progression. A-FABP is a lipid binding protein playing a role in intracellular lipid transport and metabolism, as well as in signal transduction. We reported from bladder tumors that decrease of A-FABP transcript level significantly correlated to tumor stage and to histologic grade (p < 0.05). Namely, in poor prognosis high grade pT1 tumors there was a loss of A-FABP expression compared to good prognosis tumors suggesting that re-expression of A-FABP could be a therapeutic approach in early stage bladder cancer to prevent disease progression. We demonstrated for the first time that this marker is upregulated by Peroxisome Proliferator-Activated Receptor (PPAR) a, b and c in T24 cells (derived from an undifferentiated grade III carcinoma) and only by PPARb in RT4 cells (derived from a well differentiated grade I papillary tumor). This effect occurred through a PPAR-dependent transcriptional mechanism without modifying mRNA stability and interestingly required de novo protein synthesis. Data as a whole suggest a prognostic significance of A-FABP in bladder cancer outcome and the potential utility of overexpression of this protein by PPAR agonists open up new perspectives in the treatment of bladder cancer.

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“…The mechanism by which androgens are involved in the progression to this androgenindependent (AI) phenotype remains unclear. We and others have recently shown that upstream and parallel survival pathways of androgen synthesis such as cholesterol synthesis, lipid metabolism and fatty acid synthesis are implicated in prostate cancer progression [3][4][5][6]. Hager et al initially investigated the role of cholesterol metabolism in prostate cancer and found that during early stage development, large accumulations of membrane associated lipids developed [4].…”

Section: Introductionmentioning

confidence: 99%

“…These processes are central to cell survival and proliferation [5] and thus regulation of these metabolism enzymes may be important in the transition from androgen-dependence to androgen-independence. In this paper, we explore the effect of synthetic androgen, R1881, on cholesterol synthesis and esterification enzymes, HMG-CoA reductase and Acyl-Coenzyme A:cholesterol acyltransferase (ACAT) in an androgensensitive LNCaP cell model as well as an androgeninsensitive PC-3 cell model.…”

Section: Introductionmentioning

confidence: 99%

Androgen‐mediated cholesterol metabolism in LNCaP and PC‐3 cell lines is regulated through two different isoforms of acyl‐coenzyme A: Cholesterol Acyltransferase (ACAT)

et al. 2007

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BACKGROUND. The objective of this work was to determine the effect of an androgen agonist, R1881, on intracellular cholesterol synthesis and esterification in androgen-sensitive (AS) prostate cancer (LNCaP) cells. METHODS. We investigated the activity and expression of cholesterol metabolism enzymes, HMG-CoA-reductase and ACAT in the LNCaP and PC-3 (androgen-independent control) models. RESULTS. Microsomal PC-3 HMG-CoA-reductase activity was increased with R1881 despite having similar cholesterol levels while increased cholesterol levels in microsomes from LNCaPs treated with R1881 (Lþ) were associated with increased HMG-CoA reductase activity. Increased intracellular cholesteryl esters (CE) found in (Lþ) were not associated with an increased ACAT1 activity. There was no effect from androgen treatment on ACAT1 protein expression in theses cells; however, ACAT2 expression was induced upon R1881 treatment. In contrast, we found an increase in the in vitro ACAT1 activity in PC-3 cells treated with androgen (Pþ). Only ACAT1 expression was induced in Pþ. We further assessed the expression of STAT1a, a transcriptional activator that modulates ACAT1 expression. STAT1a expression and phosphorylation were induced in Pþ. To determine the role of the AR on ACAT1 expression and esterification, we treated PC-3 cells overexpressing the androgen receptor with R1881 (PARþ). AR expression was decreased in PARþ cells; ACAT1 protein expression and cholesterol ester levels were also decreased, however, ACAT2 remained unchanged. STAT1a expression was decreased in PARþ. CONCLUSIONS. Overall, these findings support the importance of cholesterol metabolism regulation within prostate cancer cells and unravel a novel role for STAT1a in prostate cancer metabolism.

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Androgens, lipogenesis and prostate cancer

Cited by 157 publications

References 52 publications

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

A‐FABP, a candidate progression marker of human transitional cell carcinoma of the bladder, is differentially regulated by PPAR in urothelial cancer cells

Androgen‐mediated cholesterol metabolism in LNCaP and PC‐3 cell lines is regulated through two different isoforms of acyl‐coenzyme A: Cholesterol Acyltransferase (ACAT)

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