Abstract
Background/aimsIsoalantolactone (IATL) is one of multiple isomeric sesquiterpene lactones and is isolated from inula helenium. IATL has multiple functions such as antibacterial, antihelminthic and antiproliferative activities. IATL also inhibits pancreatic cancer proliferation and induces apoptosis by increasing ROS production. However, the detailed mechanism of IATL-mediated pancreatic cancer apoptosis remains largely unknown.MethodsIn current study, pancreatic carcinoma cell lines (PANC-1, AsPC-1, BxPC-3) and a mouse xenograft model were used to determine the mechanism of IATL-mediated toxic effects.ResultsIATL (20μM) inhibited pancreatic adenocarcinoma cell lines proliferation in a time-dependent way; while scratch assay showed that IATL significantly inhibited PANC-1 scratch closure (P<0.05); Invasion assays indicated that IATL significantly attenuated pancreatic adenocarcinoma cell lines invasion on matrigel. Signal analysis showed that IATL inhibited pancreatic adenocarcinoma cell proliferation by blocking EGF-PI3K-Skp2-Akt signal axis. Moreover, IATL induced pancreatic adenocarcinoma cell apoptosis by increasing cytosolic Caspase3 and Box expression. This apoptosis was mediated by inhibition of canonical wnt signal pathway. Finally, xenograft studies showed that IATL also significantly inhibited pancreatic adenocarcinoma cell proliferation and induced pancreatic adenocarcinoma cell apoptosis in vivo.ConclusionsIATL inhibits pancreatic cancer proliferation and induces apoptosis on cellular and in vivo models. Signal pathway studies reveal that EGF-PI3K-Skp2-Akt signal axis and canonical wnt pathway are involved in IATL-mediated cellular proliferation inhibition and apoptosis. These studies indicate that IATL may provide a future potential therapy for pancreatic cancer.
Highlights
Pancreatic cancer is a pandemic disease and has increased all over the world in the past decades
IATL (20μM) inhibited pancreatic adenocarcinoma cell lines proliferation in a time-dependent way; while scratch assay showed that IATL significantly inhibited PANC-1 scratch closure (P
Signal analysis showed that IATL inhibited pancreatic adenocarcinoma cell proliferation by blocking EGF-PI3K-S-phase kinase associated protein 2 (Skp2)-Akt signal axis
Summary
Pancreatic cancer is a pandemic disease and has increased all over the world in the past decades. Pancreatic cancer has been classified into exocrine and endocrine groups. Pancreatic cancer is associated with a high death rate, poor outcome and rapid developments to later stages [2]. Pancreatic cancer is believed to be related to various epidemic factors, such as obesity, heavy alcoholic consumption, genetic causes, etc [3]. The tumorigenesis processes of pancreatic cancer may involve many signal pathways, such as TGFβ, PI3K-Akt, Wnt/β-Catenin, ROS, and cyclin-Dependent Kinase related signal pathways [4,5,6,7]. Recent studies indicate that genetic mutations, and epigenetic modifications are involved in pancreatic tumorigenesis [8, 9]
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