Asuman Deveci Ozkan1, Suleyman Kaleli1, Hacer Ilke Onen2, Mehmet Sarihan3, Gamze Guney Eskiler1, Aysel Kalayci Yigin4, Mehmet Akdogan5. 1. Department of Medical Biology, Faculty of Medicine, Sakarya University, Sakarya, Turkey. 2. Department of Medical Biology, Faculty of Medicine, Gazi University, Ankara, Turkey. 3. Department of Medical Biology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey. 4. Department of Medical Genetic, Cerrahpaşa Medical Faculty, İstanbul University, Istanbul, Turkey. 5. Department of Medical Biochemistry, Faculty of Medicine, Sakarya University, Sakarya, Turkey.
Abstract
Background: Toll-like receptors (TLRs) are often expressed in natural immune cells as well as in tumor cells. TLR4 exhibits both tumor promoting and tumor-suppressing roles and higher TLR9 expression is an important marker of poor prognosis in prostate cancer (PCa). Nobiletin (NOB) is an O-methylated flavonoid and NOB has been proven to have anti-cancer effect in PCa cells. However, there is no study in the literature investigating the potential anti-inflammatory effects of NOB on the TLR signaling pathways in cancer. Therefore, we aimed to explore the potential anti-inflammatory effects of NOB on the TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways in different types of PCa cell lines, for the first time.Material and methods: In the current study, the cytotoxic effect of NOB PC-3 (hormone-independent and metastatic) and LNCaP cells (hormone-dependent) was evaluated by WST-1 assay. Furthermore, the inhibitory effects of NOB on TLR4/TRIF/IRF3 and TLR9/IRF7signaling pathway were determined by RT-PCR, western blotting and ELISA analysis. Results: NOB demonstrated an inhibitory effect on PCa cell growth and LNCaP cells were more sensitive to NOB than PC-3 cells due to androjen receptor status. Furthermore, NOB alone could suppress TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways through the downregulation of their associated pathways (mRNA and related protein levels) and the release of IFN-α and IFN-β compared to LPS or CpG-ODN stimulated PCa cells.Conclusions: NOB potentially inhibited TLR4 and TL9-dependent signaling pathway in PCa cells. However, the efficacy of NOB was different in PCa cells due to the hormone status and aggressive features.
Background: Toll-like receptors (TLRs) are often expressed in natural immune cells as well as in tumor cells. TLR4 exhibits both tumor promoting and tumor-suppressing roles and higher TLR9 expression is an important marker of poor prognosis in prostate cancer (PCa). Nobiletin (NOB) is an O-methylated flavonoid and NOB has been proven to have anti-cancer effect in PCa cells. However, there is no study in the literature investigating the potential anti-inflammatory effects of NOB on the TLR signaling pathways in cancer. Therefore, we aimed to explore the potential anti-inflammatory effects of NOB on the TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways in different types of PCa cell lines, for the first time.Material and methods: In the current study, the cytotoxic effect of NOBPC-3 (hormone-independent and metastatic) and LNCaP cells (hormone-dependent) was evaluated by WST-1 assay. Furthermore, the inhibitory effects of NOB on TLR4/TRIF/IRF3 and TLR9/IRF7signaling pathway were determined by RT-PCR, western blotting and ELISA analysis. Results:NOB demonstrated an inhibitory effect on PCa cell growth and LNCaP cells were more sensitive to NOB than PC-3 cells due to androjen receptor status. Furthermore, NOB alone could suppress TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways through the downregulation of their associated pathways (mRNA and related protein levels) and the release of IFN-α and IFN-β compared to LPS or CpG-ODN stimulated PCa cells.Conclusions: NOB potentially inhibited TLR4 and TL9-dependent signaling pathway in PCa cells. However, the efficacy of NOB was different in PCa cells due to the hormone status and aggressive features.
Authors: Alena Liskova; Marek Samec; Lenka Koklesova; Samson M Samuel; Kevin Zhai; Raghad Khalid Al-Ishaq; Mariam Abotaleb; Vladimir Nosal; Karol Kajo; Milad Ashrafizadeh; Ali Zarrabi; Aranka Brockmueller; Mehdi Shakibaei; Peter Sabaka; Ioana Mozos; David Ullrich; Robert Prosecky; Giampiero La Rocca; Martin Caprnda; Dietrich Büsselberg; Luis Rodrigo; Peter Kruzliak; Peter Kubatka Journal: Biomed Pharmacother Date: 2021-02-25 Impact factor: 7.419