Pancreatic Cancer and Inflammation

Abstract The association between cancer and inflammation is arguably undeniable. However, it is uncertain whether inflammation leads to cancer development or oncogenic changes result in inflammatory conditions. Regardless of the debate surrounding this argument, inflammation in the immediate vicinity of the tumor promotes its development and makes inflammatory markers attractive targets both for prevention as well as treatment. This review discusses the role of inflammation in pancreatic cancer, one of the most lethal cancers with the lowest survival rates. Risk factors associated with pancreatic cancer have an underlying inflammatory pathology. The mechanisms that influence cellular damage including signaling pathways in pancreatitis and pancreatic cancer will be briefly discussed

YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin

Epithelial-to-mesenchymal transition (EMT) plays an important role in prostate cancer (PCa) metastasis. The transcription/translation regulatory Y-box binding protein-1 (YB-1) is known to be associated with cancer metastasis. We observed that YB-1 expression increased with tumor grade and showed an inverse relationship with E-cadherin in a human PCa tissue array. Forced YB-1 expression induced a mesenchymal morphology that was associated with down regulation of epithelial markers. Silencing of YB-1 reversed mesenchymal features and decreased cell proliferation, migration and invasion in PCa cells. YB-1 is activated directly via Akt mediated phosphorylation at Ser102 within the cold shock domain (CSD). We next identified fisetin as an inhibitor of YB-1 activation. Computational docking and molecular dynamics suggested that fisetin binds on the residues from β1 - β4 strands of CSD, hindering Akt’s interaction with YB-1. Calculated free binding energy ranged from -11.9845 to -9.6273 kcal/mol. Plasmon Surface Resonance studies showed that fisetin binds to YB-1 with an affinity of approximately 35 µM, with both slow association and dissociation. Fisetin also inhibited EGF induced YB-1 phosphorylation and markers of EMT both in vitro and in vivo. Collectively our data suggest that YB-1 induces EMT in PCa and identify fisetin as an inhibitor of its activation

Suppression of Ultraviolet B Exposure-Mediated Activation of NF-κB in Normal Human Keratinocytes by Resveratrol

Chemoprevention by naturally occurring agents is a newer dimension in the management of neoplasia, including skin cancer. Solar ultraviolet (UV) radiation is the major cause of skin cancer. We recently demonstrated that resveratrol (3,5,4′-trihydroxystilbene), a polyphenolic antioxidant found in grapes and red wine, imparts protection from UVB-mediated cutaneous damages in SKH-1 hairless mice. The mechanism of action of resveratrol is not clearly understood. Here, we investigated the involvement of nuclear factor kappa B (NF-κB), which is known to play a critical role in skin biology and the development of skin cancer, as the mechanism of chemoprevention of UV damage by resveratrol. In the normal human epidermal keratinocytes, resveratrol blocked UVB-mediated (40 mJ/cm(2)) activation of NF-κB in a dose-dependent (5, 10, and 25 µM resveratrol for 24 hours) as well as time-dependent (5 µM resveratrol for 12, 24, and 48 hours) fashion. Resveratrol treatment of keratinocytes also inhibited UVB-mediated 1) phosphorylation and degradation of IκBα, and 2) activation of IKKα. We suggest that NF-κB pathway plays a critical role in the chemopreventive effects of resveratrol against the adverse effects of UV radiation including photocarcinogenesis