Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer

Our data demonstrated that SFN inhibited cell proliferation and colony formation, and induced apoptosis through caspase-3 activation in pancreatic cancer cells. The inhibition of PI3K/AKT and MEK/ERK pathways activated FOXO transcription factors. SFN inhibited phosphorylation of AKT and ERK, and activated FOXO transcription factors, leading to cell cycle arrest and apoptosis. Phosphorylation deficient mutants of FOXO proteins enhanced FOXO transcriptional activity, and further enhanced SFN-induced FOXO activity and apoptosis. SFN induced the expression of p21/CIP1 and p27/KIP1, and inhibited the expression of cyclin D1.These data suggest that inhibition of PI3K/AKT and ERK pathways acts together to activate FOXO transcription factor and enhances SFN-induced FOXO transcriptional activity, leading to cell cycle arrest and apoptosis.Cancer of the pancreas is the fourth leading cause of cancer death in the United States. This year approximately 32,000 Americans will die from cancer of the pancreas. With an overall 5-year survival rate of 3% [1], pancreatic cancer has one of the poorest prognoses among all cancers [2]. Only 20% of pancreatic cancer patients are eligible for surgical resection, which currently remains the only potentially curative therapy [3]. Unfortunately, many cancers of the pancreas are not resectable at the time of diagnosis. There are limited treatment options available for this disease because chemo- and radio-therapies are largely ineffective, and metastatic disease frequently redevelops even after surgery [1,2]. Therefore, developing effective strategies to prevent pancreatic neoplasms are of paramount importance.Sulforaphane (SFN), a constituent of cruciferous vegetables, is a naturally occurring isothiocyanate with promising chemopreventive activity [4]. Epidemiological studies have shown that people who eat cruciferous vegetables have reduced incidence of breast and prostate cancer. SFN possesses anti-oxidant, anti-proliferative and anti-carci