Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts

Zhuang, Liyan; Kim, Jayoung; Adam, Rosalyn M.; Solomon, Keith R.; Freeman, Michael R.

doi:10.1172/jci200519935

Cited by 457 publications

(209 citation statements)

References 55 publications

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“…Several other large studies, including the Cancer Prevention II Study, the California Men’s Health Study and a Finnish population study, also showed an association between statin use and a reduced risk of advanced prostate cancer [16–18]. The biological mechanism of action for these findings is unclear; however, theoretically, statins may protect against prostate cancer by interfering with the cholesterol‐rich domains in the cell membrane (‘lipid rafts’) that are responsible for intracellular signalling [19]. In addition, cholesterol is a precursor for androgen synthesis, and statin use, which lowers cholesterol, may decrease androgen levels thereby inhibiting tumour growth in prostate cancer cells [20].…”

Section: Discussionmentioning

confidence: 99%

Effect of statin use on biochemical outcome following radical prostatectomy

et al. 2011

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Study Type – Prognosis (retrospective cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Statin use may reduce the risk of developing prostate cancer. Studies also suggest that the protective effect of statins may be beneficial for prostate cancer patients following treatment. Statin users may also have lower PSA than non‐users. Our study agrees with the findings that statin users may have lower PSA than non‐users. Contrary to the findings that statins are protective in prostate cancer this study shows no benefit and possible worse biochemical outcome after radical prostatectomy. OBJECTIVE • To determine the relationship between statin use and biochemical recurrence (BCR) following radical prostatectomy (RP). PATIENTS AND METHODS • A retrospective analysis was performed on 3198 RP patients between 1990 and 2008. • Exclusion criteria were neo‐adjuvant or adjuvant therapy, follow‐up <2 years, and insufficient pathological or prostate‐specific antigen (PSA) data. • Statin use was determined from the patient’s record. Clinical and pathological variables were compared between statin users and non‐users. • Kaplan–Meier and multivariate Cox regression analyses were performed to determine the effect of statin use on BCR. RESULTS • A total of 1261 patients fit criteria for analysis. There were 281 (22%) statin users. Mean age was 60 years and median follow‐up was 36 months (mean 43 months). • Statin users had a lower median preoperative PSA (6.4) compared with non‐users (7.1) (P < 0.05). In all, 80% of statin users had a pathological Gleason sum ≥7 compared with 67% of non‐users (P < 0.05). • On multivariate analysis, statin use was an independent predictor of BCR (hazard ratio 1.54, P < 0.05). Statin users had a lower 5‐year BCR‐free survival compared with non‐users (75% vs 84%, P < 0.05). CONCLUSIONS • Statin users are at an increased risk for BCR following RP. This finding may be due to the reduction in preoperative PSA potentially delaying diagnosis and/or masking aggressive disease. • Further studies are necessary to elucidate the impact of statin medications following prostate cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Effect of statin use on biochemical outcome following radical prostatectomy

et al. 2011

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“…Inhibition of the mevalonate pathway blocks the synthesis of isoprenoid molecules (farnesyl pyrophosphate and geranylgeranyl pyrophosphate) that facilitate post-translational modification and activate Ras, Rac, and Rho GTPases molecules contributing to tumor proliferation (Zhuang et al, 2005; Solomon et al, 2009; Gorin et al, 2012). While statin therapy blocks the intracellular synthesis of cholesterol, it also alters the cholesterol content of tumor cell membranes, interfering with key signaling pathways (Zhuang et al, 2005). …”

Section: Cholesterol and Cancermentioning

confidence: 99%

“…In agreement with these findings recent analysis of prostate cancer animal models revealed that elevations of plasma cholesterol cause accumulations of cholesterol in lipid rafts and consequently leads to reduced apoptosis and increased tumor growth via Akt signaling (Li and Park, 2006; Adam et al, 2007; Llaverias et al, 2011; Pelton et al, 2012). In addition, increasing cholesterol levels in lipid-rafts appears to enhance Akt signaling both in vitro and in vivo and therefore inducing (cancer) cell survival (Zhuang et al, 2005). Recent studies also show that the subpopulation of Akt present in lipid rafts shows significantly higher substrate specificity compared to the normal Akt (Pommier et al, 2010).…”

Section: Cholesterol and Cancermentioning

confidence: 99%

The role of cholesterol metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics

Cruz

McConathy³

et al. 2013

Front. Pharmacol.

273

234

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While the unique metabolic activities of malignant tissues as potential targets for cancer therapeutics has been the subject of several recent reviews, the role of cholesterol metabolism in this context is yet to be fully explored. Cholesterol is an essential component of mammalian cell membranes as well as a precursor of bile acids and steroid hormones. The hypothesis that cancer cells need excess cholesterol and intermediates of the cholesterol biosynthesis pathway to maintain a high level of proliferation is well accepted, however the mechanisms by which malignant cells and tissues reprogram cholesterol synthesis, uptake and efflux are yet to be fully elucidated as potential therapeutic targets. High and low density plasma lipoproteins are the likely major suppliers of cholesterol to cancer cells and tumors, potentially via receptor mediated mechanisms. This review is primarily focused on the role(s) of lipoproteins in carcinogenesis, and their future roles as drug delivery vehicles for targeted cancer chemotherapy.

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“…In addition, data from our laboratory and others have demonstrated that Akt activity and cell survival are dependent on cholesterol content. Lowering cellular cholesterol, either by cholesterol depletion or inhibition of synthesis, results in Akt inactivation and cell death, further indicating that the integrity of rafts and caveolae are critical for cell survival signalling involving Akt activation (Zhuang et al ., 2002; Zhuang et al ., 2005).…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by the ginsenoside Rh2 by internalization of lipid rafts and caveolae and inactivation of Akt

Park

Lee

et al. 2010

British J Pharmacology

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Background and purpose: Lipid rafts and caveolae are membrane microdomains with important roles in cell survival signalling involving the Akt pathway. Cholesterol is important for the structure and function of these microdomains. The ginsenoside Rh2 exhibits anti-tumour activity. Because Rh2 is structurally similar to cholesterol, we investigated the possibility that Rh2 exerted its anti-tumour effect by modulating rafts and caveolae. Experimental approach: A431 cells (human epidermoid carcinoma cell line) were treated with Rh2 and the effects on cell apoptosis, raft localization and Akt activation measured. We also examined the effects of over-expression of Akt and active-Akt on Rh2-induced cell death. Key results: Rh2 induced apoptosis concentration-and time-dependently. Rh2 reduced the levels of rafts and caveolae in the plasma membrane and increased their internalization. Furthermore, Akt activity was decreased and consequently, Aktdependent phosphorylation of Bad, a pro-survival protein, was decreased whereas the pro-apoptotic proteins, Bim and Bax, were increased upon Rh2 treatment. Unlike microdomain internalization induce by cholesterol depletion, Rh2-mediated internalization of rafts and caveolae was not reversed by cholesterol addition. Also, cholesterol addition did not restore Akt activation or rescue cells from Rh2-induced cell death. Rh2-induced cell death was attenuated in MDA-MB-231 cells overexpressing either wild-type or dominant-active Akt. Conclusions and implications: Rh2 induced internalization of rafts and caveolae, leading to Akt inactivation, and ultimately apoptosis. Because elevated levels of membrane rafts and caveolae, and Akt activation have been correlated with cancer development, internalization of these microdomains by Rh2 could potentially be used as an anti-cancer therapy.

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Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts

Cited by 457 publications

References 55 publications

Effect of statin use on biochemical outcome following radical prostatectomy

Effect of statin use on biochemical outcome following radical prostatectomy

The role of cholesterol metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics

Induction of apoptosis by the ginsenoside Rh2 by internalization of lipid rafts and caveolae and inactivation of Akt

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