The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer

Stine, Jessica E.; Guo, Hui; Sheng, Xiugui; Han, Xiaozhe; Schointuch, M.; Gilliam, Timothy P.; Gehrig, Paola A.; Zhou, Chunxiao; Bae‐Jump, Victoria L.

doi:10.18632/oncotarget.5834

Cited by 72 publications

(67 citation statements)

References 53 publications

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“…It has recently been reported that obesity and subsequent hyperlipidemia are critical prognostic factors in EOC (35,36), and that statins, which are antihyperlipidemic agents, are expected to improve EOC prognosis (37). Interestingly, hLSR, which we identified as a new target in EOC, is related to lipid metabolism.…”

Section: Discussionmentioning

confidence: 82%

LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake

et al. 2018

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Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum. To evaluate the possible benefits of blocking this antigen in EOC, we raised a new monoclonal antibody (mAb) to human LSR (hLSR). In mouse xenograft models of hLSR EOC (cell lines or patient-derived tumors), we found that administration of anti-hLSR mAb inhibited tumor growth in a manner independent of both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Mechanistic investigations showed that hLSR expression increased incorporation of very-low-density lipoprotein (VLDL) into EOC cells and that anti-hLSR mAb inhibited lipid uptake and Moreover, VLDL promoted cell proliferation in hLSR-positive EOC cells , and this effect was inhibited by anti-hLSR mAb. While the anti-hLSR mAb studied cross reacted with the mouse antigen, we observed no adverse effects on normal organs and lipid metabolism in murine hosts. Our findings suggest that hLSR plays a key functional role in EOC development and that this antigen can be therapeutically targeted by specific mAb to improve EOC treatment. These findings offer preclinical evidence of the therapeutic efficacy of a novel targeted antibody therapy against deadly epithelial ovarian cancers. .

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Section: Discussionmentioning

confidence: 82%

LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake

et al. 2018

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“…HMGCR is the rate-limiting enzyme in de novo synthesis of cholesterol in vivo. Recent studies have reported that HMGCR is upregulated in several types of cancer including gastric [34], ovarian [7] and breast cancers [35], suggesting that HMGCR plays an oncogenic role. SREBF2 is a membrane-bound transcription factor that regulates cholesterol homeostasis in cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, many studies have demonstrated that cholesterol accumulate in a series of human cancers, including breast [2], colon [3], prostate [4], HCC [5], and others [6]. In addition, enzymes involved in cholesterol metabolism have been reported abnormal expression in cancer tissues [7, 8]. For instance, cholesterol acyltransferase (ACAT)2, is found to be induced and promotes esterification of excess oxysterols for secretion to avoid cytotoxicity in a subset of hepatocellular carcinomas (HCCs) for tumor growth [9], suggestive of a specific cholesterol metabolic pathway in HCCs.…”

Section: Introductionmentioning

confidence: 99%

Pro-inflammation NF-κB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells

Zhang²,

Dong

et al. 2017

J Exp Clin Cancer Res

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BackgroundHepatocellular carcinoma (HCC) develops in a complex microenvironment characterized by chronic inflammation. In recent years, cholesterol metabolic abnormalities have been implicated the importance in cancer cell physiology. This study was designed to investigate the relationship between inflammation and cholesterol accumulation in HCC cells.MethodsHuman HCC cells HepG2 and Huh7 were cultured and stimulated with lipopolysaccharide (LPS) for 24 h. The changes of HCC cells related to cholesterol metabolism including intracellular cholesterol concentrations, cholesterol uptake, and the expression of cholesterol-related genes 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), LDL receptor (LDLR), sterol regulatory element-binding transcription factor 2 (SREBF2), and proprotein convertase subtilisin/kexin 9 (PCSK9) were comparatively analyzed. Simultaneously, the effects of nuclear factor-kappa B (NF-κB) signaling pathway on cholesterol metabolism were clarified by knocking-down of nuclear factor kappa-B kinase subunit alpha (IKKα) and TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 (TAB3) via RNAi and microRNA (miR)-195. Subsequently, the roles of cholesterol accumulation in LPS induced pro-inflammatory effects were further investigated.ResultsPro-inflammatory factor LPS significantly increased intracellular cholesterol accumulation by upregulating the expression of HMGCR, LDLR, and SREBF2, while downregulating the expression of PCSK9. These effects were revealed to depend on NF-κB signaling pathway by knocking-down and overexpression of IKKα and TAB3. Additionally, miR-195, a regulator directly targeting IKKα and TAB3, blocked the effects of cholesterol accumulation, further supporting the critical role of pro-inflammation NF-κB signaling in regulating cholesterol accumulation. Intriguingly, the accumulation of cholesterol conversely exerted an augmented pro-inflammation effects by further activating NF-κB signaling pathway.ConclusionsThese results indicated that pro-inflammation effects of NF-κB signaling could be augmented by a positive feedback via enhancing the cholesterol accumulation in liver cancer cells.

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“…Interestingly, preclinical studies have found that statins also have antineoplastic potential through the induction of tumor cell apoptosis and inhibition of tumor cell proliferation, invasion, and migration [8–10]. These effects have also been shown in ovarian and endometrial cancer-derived cell lines [11–12]. Indeed, a body of epidemiologic studies has demonstrated that statins are associated with improved survival outcomes in several malignancies, including breast, gastric, colorectal, prostate, and kidney cancer [13–17].…”

Section: Introductionmentioning

confidence: 99%

Statin use and survival outcomes in endocrine-related gynecologic cancers: A systematic review and meta-analysis

Xie

Huang

et al. 2017

Oncotarget

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Previous studies investigating the association between statin use and survival outcomes in gynecologic cancers have yielded controversial results. We conducted a systematic review and meta-analysis to evaluate the association based on available evidence. We searched the databases of the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and PubMed from inception to January 2017. Studies that evaluated the association between statin use and survival outcomes in gynecologic cancers were included. Pooled hazard ratios (HRs) for overall survival, disease-specific survival and progression-free survival were calculated using a fixed-effects model. A total of 11 studies involving more than 6,920 patients with endocrine-related gynecologic cancers were identified. In a meta-analysis of 7 studies involving 5,449 patients with endocrine-related gynecologic cancers, statin use was linked to improved overall survival (HR, 0.71; 95% confidence interval [CI], 0.63 to 0.80) without significant heterogeneity (I2 = 33.3%). Statin users also had improved disease-specific survival (3 studies, HR, 0.72; 95% CI, 0.58 to 0.90, I2 = 35.1%) and progression-free survival (3 studies, HR, 0.68; 95% CI, 0.49 to 0.93, I2 = 33.6%) in endocrine-related gynecologic cancers. Our findings support that statin use has potential survival benefits for patients with endocrine-related gynecologic cancers. Further large-scale prospective studies are required to validate our findings.

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The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer

Cited by 72 publications

References 53 publications

LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake

LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake

Pro-inflammation NF-κB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells

Statin use and survival outcomes in endocrine-related gynecologic cancers: A systematic review and meta-analysis

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