Prediagnosis Use of Statins Associates With Increased Survival Times of Patients With Pancreatic Cancer

Hamada, Tsuyoshi; Khalaf, Natalia; Yuan, Chen; Morales-Oyarvide, Vicente; Babić, Ana; Nowak, Jonathan A.; Qian, Zhi Rong; Ng, Kimmie; Rubinson, Douglas A.; Kraft, Peter; Giovannucci, Edward; Stampfer, Meir J.; Fuchs, Charles S.; Ogino, Shuji; Wolpin, Brian M.

doi:10.1016/j.cgh.2018.02.022

Cited by 21 publications

(13 citation statements)

References 45 publications

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“…The finding that atorvastatin suppresses ADM and, when combined with BET inhibition, can reduce tumor growth aligns with an extensive epidemiologic literature that suggest that statins, which are widely prescribed clinically as cholesterol-lowering agents, may also exert anticancer effects (55). Although analysis of two large prospective studies found no difference in pancreatic cancer risk between regular and non-regular statin users (56), a modest increase in median survival was observed for patients who had been regular statin users for the 2 years prior to cancer diagnosis (57). In addition, numerous prior studies have found that statin use correlates with extended survival, particularly if precedent to pancreatic cancer diagnosis and in a high-dose regimen (55).…”

Section: Researchmentioning

confidence: 57%

Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis

et al. 2019

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Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS -mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specifi c loss of the acetyl-CoA-producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT-ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA-dependent processes exerts anticancer effects. SIGNIFICANCE :Pancreatic cancer is among the deadliest of human malignancies. We identify a key role for the metabolic enzyme ACLY, which produces acetyl-CoA, in pancreatic carcinogenesis. The data suggest that acetyl-CoA use for histone acetylation and in the mevalonate pathway facilitates cell plasticity and proliferation, suggesting potential to target these pathways. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A. Carrer, S. Trefely,

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Section: Researchmentioning

confidence: 57%

Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis

et al. 2019

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“…In line with this conclusion, recent epidemiological studies imply that the use of statins is associated with beneficial effects in PDAC [38–47], and other malignancies [48]. Although a recent study failed to detect an effect of statins in lowering PDAC risk [73], a follow up study of the same data reported an increased survival in PDAC patients with regular pre-diagnosis use of statins [74]. Taken together with the findings presented here and the lack of efficient strategies to oppose PDAC development, these studies warrant a comprehensive evaluation of the lipophilic statins in the primary or secondary chemoprevention of this devastating disease.…”

Section: Discussionmentioning

confidence: 85%

Lipophilic statins inhibit YAP nuclear localization, co-activator activity and colony formation in pancreatic cancer cells and prevent the initial stages of pancreatic ductal adenocarcinoma in KrasG12D mice

Hao

Wang

et al. 2019

PLoS ONE

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We examined the impact of statins on Yes-associated Protein (YAP) localization, phosphorylation and transcriptional activity in human and mouse pancreatic ductal adenocarcinoma (PDAC) cells. Exposure of sparse cultures of PANC-1 and MiaPaCa-2 cells to cerivastatin or simvastatin induced a striking re-localization of YAP from the nucleus to the cytoplasm and inhibited the expression of the YAP/TEAD-regulated genes C onnective T issue G rowth F actor ( CTGF) and Cysteine-rich angiogenic inducer 61 ( CYR61 ). Statins also prevented YAP nuclear import and expression of CTGF and CYR61 stimulated by the mitogenic combination of insulin and neurotensin in dense culture of these PDAC cells. Cerivastatin, simvastatin, atorvastatin and fluvastatin also inhibited colony formation by PANC-1 and MiaPaCa-2 cells in a dose-dependent manner. In contrast, the hydrophilic statin pravastatin did not exert any inhibitory effect even at a high concentration (10 μM). Mechanistically, cerivastatin did not alter the phosphorylation of YAP at Ser 127 in either PANC-1 or MiaPaCa-2 cells incubated without or with neurotensin and insulin but blunted the assembly of actin stress fiber in these cells. We extended these findings with human PDAC cells using primary KC and KPC cells, (expressing KrasG12D or both KrasG12D and mutant p53, respectively) isolated from KC or KPC mice. Using cultures of these murine cells, we show that lipophilic statins induced striking YAP translocation from the nucleus to the cytoplasm, inhibited the expression of Ctgf , Cyr61 and Birc5 and profoundly inhibited colony formation of these cells. Administration of simvastatin to KC mice subjected to diet-induced obesity prevented early pancreatic acini depletion and PanIN formation. Collectively, our results show that lipophilic statins restrain YAP activity and proliferation in pancreatic cancer cell models in vitro and attenuates early lesions leading to PDAC in vivo .

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“…the cholesterol reducing drugs called statins, lower the levels of farnesyl substrate and reduce the amount of K-RAS that can localize in the PM [3]. Many published meta-analyses have shown that statin use enhances the survival time of pancreatic cancer patients, with one study also linking the AMPK activator metformin to prolonged survival [6][7][8][9][10]. Maintenance of K-RAS on the PM additionally requires the chaperone protein PDEδ [11].…”

Section: Introductionmentioning

confidence: 99%

Neratinib inhibits Hippo/YAP signaling, reduces mutant K-RAS expression, and kills pancreatic and blood cancer cells

et al. 2019

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Prior studies demonstrated that the irreversible ERBB1/2/4 inhibitor neratinib caused plasma membrane-associated mutant K-RAS to localize in intracellular vesicles, concomitant with its degradation. Herein, we discovered that neratinib interacted with the chemically distinct irreversible ERBB1/2/4 inhibitor afatinib to reduce expression of ERBB1, ERBB2, K-RAS and N-RAS; this was associated with greater-than-additive cell killing of pancreatic tumor cells. Knock down of Beclin1, ATG16L1, Rubicon or cathepsin B significantly lowered the ability of neratinib to reduce ERBB1 and K-RAS expression, and to cause tumor cell death. Knock down of ATM-AMPK suppressed vesicle formation and knock down of cathepsin B-AIF significantly reduced neratinib lethality. PKG phosphorylates K-RAS and HMG CoA reductase inhibitors reduce K-RAS farnesylation both of which remove K-RAS from the plasma membrane, abolishing its activity. Neratinib interacted with the PKG activator sildenafil and the HMG CoA reductase inhibitor atorvastatin to further reduce K-RAS expression, and to further enhance cell killing. Neratinib is also a Ste20 kinase family inhibitor and in carcinoma cells, and hematopoietic cancer cells lacking ERBB1/2/4, it reduced K-RAS expression and the phosphorylation of MST1/3/4/ Ezrin by ~30%. Neratinib increased LATS1 phosphorylation as well as that of YAP and TAZ also by ~30%, caused the majority of YAP to translocate into the cytosol and reduced YAP/TAZ #

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Prediagnosis Use of Statins Associates With Increased Survival Times of Patients With Pancreatic Cancer

Abstract: Regular statin use before diagnosis of pancreatic cancer was associated with modest increases in survival times in 2 large prospective cohort studies.

Cited by 21 publications

References 45 publications

Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis

Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis

Lipophilic statins inhibit YAP nuclear localization, co-activator activity and colony formation in pancreatic cancer cells and prevent the initial stages of pancreatic ductal adenocarcinoma in KrasG12D mice

Neratinib inhibits Hippo/YAP signaling, reduces mutant K-RAS expression, and kills pancreatic and blood cancer cells

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