Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48^Cre/+ LSL‐Kras^G12D/+ mice

Abstract

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 p48Cre/+-LSL-KrasG12D/+ transgenic mice. Six-week old male p48Cre/+-LSL-KrasG12D/+ (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.

Statins and pancreatic cancer

“…Simvastatin and atorvastatin have been shown to significantly delay the progression of PanIN lesions to PDAC and to inhibit PDAC growth in conditional K-Ras mutant mice (57,58). In one study, treatment with atorvastatin resulted in significantly downregulated expression of components of the Ras/MAPK, phosphoinositide 3-kinase (PI3K)/Akt and nuclear factor-κB (NF-κB) signaling pathways, including Akt, phosphorylated (p) Akt, purinergic receptor P2X7, RhoA, pERK, cyclin dependent kinase 2, cyclin D1, β-catenin, cyclin E, survivin, caveolin-1, granulocyte-macrophage colony-stimulating factor, cyclooxygenase-2 (COX-2), and interleukin (IL)-2, -6 and -12 in vivo ( Fig.…”

New insights into pancreatic cancer stem cells

“…Hence, developing novel strategies to delay or inhibit progression of pancreatic cancer targeting CSCs are warranted. The K-rasG12D genetically engineered mouse (GEM) is an excellent model that shows the development of lesions closely resembling human PanIN's with progression to PDAC and it has been used successfully for chemoprevention studies [5,8,[72][73][74][75][76][77][78] . We have shown that licofelone, a dual COX-5-LOX inhibitor, exhibits chemopreventive efficacy against pancreatic cancer in p48…”

Anti-cancer potential of MAPK pathway inhibition in paragangliomas – effect of different statins on mouse pheochromocytoma cells

“…The extent of the anti-cancer effects has been shown to vary depending on model and type of statin used [24][25][26][27][28][29][30]. Thus, we evaluated which of the seven currently available statins may be most effective for PHEO/PGL treatment.…”