Abstract
Pancreatic cancer is a deadly disease, and therefore effective treatment and/or prevention strategies are urgently needed. The objectives of this study were to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer cell growth in vitro, and xenografts in Balb C nude mice, and pancreatic cancer cell growth isolated from KrasG12D transgenic mice. XTT assays were performed to measure cell viability. AsPC-1 cells were injected subcutaneously into Balb c nude mice and treated with embelin. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of Akt, and Sonic Hedgehog (Shh) and their target gene products were measured by the immunohistochemistry, and Western blot analysis. The effects of embelin on pancreatic cancer cells isolated from 10-months old KrasG12D mice were also examined. Embelin inhibited cell viability in pancreatic cancer AsPC-1, PANC-1, MIA PaCa-2 and Hs 766T cell lines, and these inhibitory effects were blocked either by constitutively active Akt or Shh protein. Embelin-treated mice showed significant inhibition in tumor growth which was associated with reduced expression of markers of cell proliferation (Ki67, PCNA and Bcl-2) and cell cycle (cyclin D1, CDK2, and CDK6), and induction of apoptosis (activation of caspase-3 and cleavage of PARP, and increased expression of Bax). In addition, embelin inhibited the expression of markers of angiogenesis (COX-2, VEGF, VEGFR, and IL-8), and metastasis (MMP-2 and MMP-9) in tumor tissues. Antitumor activity of embelin was associated with inhibition of Akt and Shh pathways in xenografts, and pancreatic cancer cells isolated from KrasG12D mice. Furthermore, embelin also inhibited epithelial-to-mesenchymal transition (EMT) by up-regulating E-cadherin and inhibiting the expression of Snail, Slug, and ZEB1. These data suggest that embelin can inhibit pancreatic cancer growth, angiogenesis and metastasis by suppressing Akt and Shh pathways, and can be developed for the treatment and/or prevention of pancreatic cancer.
Highlights
Pancreatic cancer is one of highly aggressive malignant diseases worldwide
The purpose of this study was to examine the molecular mechanisms by which embelin inhibits tumor growth, angiogenesis, and metastasis of pancreatic cancer cells xenografted in Balb C nude mice
We have demonstrated that inhibition of the Sonic Hedgehog (Shh) signaling pathway significantly inhibited epithelial-to-mesenchymal transition (EMT) by suppressing the activation of transcription factors Snail and Slug, which were correlated with significantly reduced pancreatic cancer stem cell invasion [26,27,47,49,50], suggesting that the Shh signaling pathway is involved in early metastasis
Summary
Pancreatic cancer is one of highly aggressive malignant diseases worldwide. The poor prognosis of the disease is related with late presentation, aggressive local invasion, and early metastasis. Gemcitabine is a potent anticancer drug approved for the treatment of pancreatic cancer, but the response rate is very poor. FOLFOX chemotherapy (folinic acid, 5-flurouracil and oxaliplatin) is commonly used for the treatment of pancreatic cancer with limited success. Several factors are associated with increased risk for pancreatic cancer and these include diabetes, chronic pancreatitis, prior gastric surgery, smoking, radiation, and specific gene polymorphisms [4,5]. Heritable and several acquired gene mutations (e.g. Kras) are common in pancreatic tumors [6]. Mutations in the cyclin-dependent kinase inhibitor p16, the tumor suppressor gene p53, and SMAD4 have been identified [7,8]. Understanding the pathogenesis of the preinvasive stage, and developing effective strategies to prevent and/or treat pancreatic cancer are of paramount importance
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