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Nutraceutical Inhibition of Hedgehog Signaling in Pancreatic Cancer
AdvisorStan, Silvia D
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Pancreatic cancer (PC)is the fourth leading cause of cancer-related deaths in the United States. PC is predominantly diagnosed at distant stage and is characterized as being highly chemoresistant and metastatic. Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated with cancer cell proliferation, chemoresistance, and metastasis. Dietary nutraceuticals have been identified which show inhibition of the Hh signaling pathway in PC cells, an increase in apoptosis, and a decrease in cell growth and cancer stem cell characteristics. Diallyl trisulfide (DATS) is a bioactive compound present in Allium vegetables such as garlic and onion. Our lab has previously shown that DATS inhibits cell growth and colony formation of PC cells and modulates the Hh signaling pathway including downregulation of the transcription factor Gli-1 in AsPC-1 cells. The present study expanded upon this work, further implicating DATS as a potential chemopreventive dietary agent capable of inhibiting the Hh signaling pathway in PC cells. Core components of the Hh signaling pathway (Gli-1, Gli-3, SMO, and Shh) were assessed by Western blotting, following a 24-hour treatment with 0 – 100μmol/L DATS in PC cell lines AsPC-1, BxPC-3, and MIA PaCa-2. SMO and Gli-3 protein expression in BxPC-3 cells were further assessed via immunocytochemistry. Gli-3 mRNA expression was evaluated by qRT-PCR analysis. DATS was shown to differentially modulate Hh signaling in PC cell lines. A significant reduction in the levels of Hh signaling proteins was detected in AsPC-1 (Gli-1) and BxPC-3 (Gli-1, and Gli-3) cells suggesting inhibition of the pathway. This study supports further investigation of DATS as a potentially chemopreventive dietary agent for PC.