jsh-23 and Ovarian-Neoplasms

As widely used in consumer products, perfluorooctanoic acid (PFOA) has become a common environmental pollutant, which has been detected in human serum and associated with cancers. Our previous study showed that PFOA is a carcinogen that promotes endometrial cancer cell migration and invasion through activation of ERK/mTOR signaling. Here, we showed that PFOA (≥100 nM) treatment also stimulated A2780 ovarian cancer cell invasion and migration, which correlated with increased matrix metalloproteinases MMP-2/-9 expression, important proteases associated with tumor invasion and migration. Notably, PFOA treatment induced activation of ERK1/2/ NF-κB signaling. Pre-treatment with U0126, an ERK1/2inhibitor；or JSH-23, a NF-kB inhibitor, can reverse the PFOA-induced cell migration and invasion. Consistent with these results, inhibiting ERK1/2 or NF-κB signaling abolished PFOA-induced up-regulation of MMP-2/-9 expression. These results indicate that PFOA can stimulate ovarian cancer cell migration, invasion and MMP-2/-9 expression by up-regulating ERK/NF-κB pathway.

Topics: Active Transport, Cell Nucleus; Apoptosis; Butadienes; Caprylates; Carcinogens, Environmental; Cell Line, Tumor; Cell Movement; Enzyme Induction; Female; Fluorocarbons; Humans; Kinetics; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Proteins; NF-kappa B; Nitriles; Ovarian Neoplasms; Phenylenediamines; Phosphorylation; Protein Kinase Inhibitors; Protein Processing, Post-Translational

Nuclear factor-kappa B (NF-кB) comprises a family of protein transcription factors that have a regulatory function in numerous cellular processes and are implicated in the cancer cell response to antineoplastic drugs, including cisplatin. We characterized the effects of DNA adducts of cisplatin and ineffective transplatin on the affinity of NF-кB proteins to their consensus DNA sequence (кB site). Although the кB site-NF-κB protein interaction was significantly perturbed by DNA adducts of cisplatin, transplatin adducts were markedly less effective both in cell-free media and in cellulo using a decoy strategy derivatized-approach. Moreover, NF-κB inhibitor JSH-23 [4-methyl-N¹-(3-phenylpropyl)benzene-1,2-diamine] augmented cisplatin cytotoxicity in ovarian cancer cells and the data showed strong synergy with JSH-23 for cisplatin. The distinctive structural features of DNA adducts of the two platinum complexes suggest a unique role for conformational distortions induced in DNA by the adducts of cisplatin with respect to inhibition of the binding of NF-кB to the platinated кB sites. Because thousands of κB sites are present in the DNA, the mechanisms underlying the antitumor efficiency of cisplatin in some tumor cells may involve downstream processes after inhibition of the binding of NF-κB to κB site(s) by DNA adducts of cisplatin, including enhanced programmed cell death in response to drug treatment.

Topics: Antineoplastic Agents; Base Sequence; Binding Sites; Cell Line, Tumor; Cisplatin; Consensus Sequence; DNA Adducts; DNA, Neoplasm; Drug Synergism; Female; HEK293 Cells; Humans; NF-kappa B; Nucleic Acid Conformation; Ovarian Neoplasms; Phenylenediamines; Stereoisomerism