Abstract
Human pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer type with a very high mortality rate. Inflammatory cytokine such as tumor necrosis factor- alpha (TNF-α) plays a pivotal role in the progression of PDAC. Recently, suppression of cell invasion by preventive agents has received considerable attention in the prevention of metastatic tumors. Several clinical studies suggested that natural forms or analogues of fat-soluble vitamins such as vitamin A and vitamin D can work as anti-cancer agents to inhibit the development of cancer. In this study, our results demonstrated that co-treatment of 13-cis retinoic acid (13-cis RA) and 1,25-dihydroxyvitamin D3 (1,25-VD3) significantly inhibited TNF-α mediated cell invasion in PDAC in vitro. Cotreatment of 13-cis RA and 1,25-VD3 also inhibited TNF-α mediated expression of matrix metalloproteinase-9 (MMP-9) protein through blocking c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-κB) signaling pathways. Our results demonstrated that treatment of TNF-α lead to a decreased expression of tissue inhibitor of metalloproteinase- 3 (TIMP-3) protein and an induction of MMP-9 protein and cell invasion through an upregulation of microRNA-221 (miR-221) in human PDAC cells. Moreover, treatment of SP600125 (a specific inhibitor of JNK pathway) or cotreatment of 13-cis RA and 1,25-VD3 significantly induced a decreased expression of miR-221 and an increased expression of TIMP-3 protein. These results suggest that 13-cis RA and 1,25-VD3 significantly suppress TNF-α mediated cell invasion and therefore potentially act as preventive agents against PDAC.
Highlights
Pancreatic cancer is a deadly cancer type and featured with extremely poor prognosis in the world [1]
Our results showed that co-treatment of 13-cis-retinoic acid (RA) and 1, 25-VD3 could significantly inhibit the activation of Jun N-terminal kinase (JNK) and nuclear factor kappa-B (NF-κB) signaling pathways through decreased phosphorylation levels of JNK and IκBα proteins in the cytoplasm of human Pancreatic ductal adenocarcinoma (PDAC) cells (Fig 3C)
Cotreatment of 13-cis RA and 1, 25-VD3 reduced the nuclear levels of Rel A (p65 NF-κB), c-fos and phosphorylated- c-Jun proteins (AP-1 protein) in human PDAC cells (Fig 3D). These results suggested that co-treatment of 13-cis RA and 1, 25-VD3 potentially inhibited tumor necrosis factor- α (TNF-α)- mediated expression of matrix metalloproteinase-9 (MMP-9) protein, in part, through blockade of JNK and NF-κB signaling pathways in human PDAC cells
Summary
Pancreatic cancer is a deadly cancer type and featured with extremely poor prognosis in the world [1]. Several studies indicate that cancer microenvironment such as cytokines and matrix metalloproteinases (MMPs) play important roles in the progression and metastasis of pancreatic cancer [3] Among these cytokines, tumor necrosis factor- alpha (TNF-α) is a key inflammatory cytokine and involves in the inflammatory response during tumor development [4]. A study indicated that low level of vitamin D receptor (VDR) was correlated with poor prognosis and survival rate in pancreatic cancer patients [25]. These evidences suggested that retinoids and vitamin D might play important roles in the prevention of tumor progression in advanced pancreatic cancer patients. We investigated the chemo-preventive effects and mechanisms of action of 13-cis RA and 1, 25-VD3 on the prevention of cell invasion and MMP expression in PDAC cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
