Academic Journal
Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48 Cre/+ LSL‐Kras G12D/+ mice
| العنوان: | Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48 Cre/+ LSL‐Kras G12D/+ mice |
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| المؤلفون: | Mohammed, Altaf, Qian, Li, Janakiram, Naveena B., Lightfoot, Stan, Steele, Vernon E., Rao, Chinthalapally V. |
| المصدر: | International Journal of Cancer ; volume 131, issue 8, page 1951-1962 ; ISSN 0020-7136 1097-0215 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2012 |
| المجموعة: | Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: | Pancreatic cancer is the one of most common causes of cancer deaths and has the worst prognosis. Clinical observational studies suggest that statins may reduce the risk of pancreatic cancer. The chemopreventive efficacy of the statin atorvastatin (Lipitor ® ) and the role of the phosphatidyl‐inositol 3‐kinase (PI3/AKT) signaling pathway were evaluated for the progression of pancreatic intraepithelial neoplasms (PanINs) to pancreatic ductal adenocarcinoma (PDAC) in conditional p48 Cre/+ ‐ LSL‐ Kras G12D/+ transgenic mice. Six‐week‐old male p48 Cre/+ ‐LSL‐Kras G12D/+ (20/group) mice were fed AIN‐76A diets containing 0, 200 and 400 ppm atorvastatin for 35 weeks. At termination, pancreata were evaluated histopathologically for PanINs and PDAC, and for various PI3/AKT signaling markers, and inflammatory cytokines, by immunohistochemistry/immunohistoflourscence, ELISA, Western blotting and/or reverse transcription‐PCR methods. Control diet‐fed mice showed 85% incidence of PDAC; whereas, mice fed with atorvastatin showed PDAC incidence of 65 and 35%, respectively ( p < 0.0001). Similarly, significant suppression of PanIN‐3 (22.6%) was observed in mice fed 400 ppm atorvastatin. Importantly, pancreata from atorvastatin‐treated mice were ∼68% free from ductal lesions. Furthermore, pancreas of mice administered with atorvastatin had significantly reduced expressions levels of PCNA, p2X7, p‐ERK, RhoA, cyclin D1, survivin, Akt, pAKT, β‐catenin, cyclin E, cdK2 and caveolin‐1. Also, atorvastatin‐treated mice had shown dose‐dependent suppression of inflammatory cytokines and a significant increase in tunnel‐positive cells, p21 and PARP expression levels in pancreas. Atorvastatin significantly delays the progression of PanIN‐1 and ‐2 lesions to PanIN‐3 and PDAC by modulating PI3/AKT signal molecules in a preclinical model, suggesting potential clinical benefits of statins for high‐risk pancreatic cancer patients. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1002/ijc.27456 |
| الاتاحة: | http://dx.doi.org/10.1002/ijc.27456 https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fijc.27456 https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.27456 |
| Rights: | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| رقم الانضمام: | edsbas.ADA025AA |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/ijc.27456 |
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