The therapy resistance of pancreatic cancer is associated with the loss of gap junction intercellular communication and connexin 43 expression. The broccoli isothiocyanate sulforaphane restored these features and therapy sensitivity. We investigated whether microRNA signaling is involved. Established cell lines and a patient tissue array (n = 96) were evaluated by miRNA and gene array, bioinformatics, expression studies, in situ hybridization and immunohistochemistry. Sulforaphane inhibited the expression of our top candidate miR30a-3p. Upon transfection of miR30a-3p inhibitors, the gemcitabine bystander effect, Cx43 expression and intercellular communication increased, whereas miR30a-3p mimics inhibited the luciferase activity of a Cx43 3'-UTR construct. miR30a-3p-overexpressing tumor xenografts had a decreased tumor volume and increased gemcitabine sensitivity. In patient tissues, a higher expression of miR30a-3p and a lower expression of Cx43 correlated with malignancy. These findings provide new knowledge and suggest sulforaphane as cotreatment for pancreatic cancer.

Silver has been in clinical use since ancient times and silver nanoparticles (AgNPs) have attracted attention in cancer therapy. We investigated the mechanisms by which AgNPs inhibit pancreatic ductal adenocarcinoma (PDAC). AgNPs were synthesized and 3 human PDAC and 2 nonmalignant primary cell lines were treated with AgNPs. MTT, MAPK, colony, spheroid and scratch assays, Western blotting, TEM, annexin V, 7-AAD, and H2DCFDA staining, FACS analysis, mRNA array and bioinformatics analyses, tumor xenograft transplantation, and immunohistochemistry of the treated cells were performed. We found that minimal AgNPs amounts selectively eradicated PDAC cells within a few hours. AgNPs inhibited cell migration and spheroid and colony formation, damaged mitochondria, and induced paraptosis-like cell death with the presence of cytoplasmic vacuoles, dilation of the ER and mitochondria, ROS formation, MAPK activity, and p62 and LC3b expression, whereas effects on the nucleus, DNA fragmentation, or caspases were not detectable. AgNPs strongly decreased tumor xenograft growth without side effects and reduced the expression of markers for proliferation and DNA repair, but upregulated paraptosis markers. The results highlight nanosilver as complementary agent to improve the therapeutic efficacy in pancreatic cancer.