exenatide and Ovarian-Neoplasms

This study investigated if EX-527 has an anti-tumour effect in SKOV-3 and OVCAR-3 ovarian cancer (OC) cell lines and if this effect involves the SIRT1/NF-κB axis. Cells were cultured in the presence or absence of EX-527, a selective SIRT-1 inhibitor. Exendin-4 significantly induced cell death in both cell lines and inhibited cell migration and invasion. Also, it decreased protein levels of Bcl-2, MMP-9, and ICAM-1 and increased those of Bax, cyclin D1 and cleaved caspase-3. Mechanistically, Exendin-4 increased the activity and nuclear accumulation of SIRT1 and decreased nuclear levels of NF-κB p65; acetylated levels of NF-κB p65, and cytoplasmic levels of p-IKKα and p-IκBα. EX-527 partially ameliorated the effect of Exendin-4 on cell death, migration, and invasion, as well as on the expression of Bcl-2, MMP-9, Bax, cleaved caspase-3 and ICAM-1. In addition, EX-527 did not affect the levels of nuclear p65 and p-p65 (Ser536); p-IκBα (Ser32) and p-IKKαβ. In conclusion, Exendin-4 can suppress OC by inhibiting NF-kB through SIRT1 dependent and independent mechanisms.

Topics: Acetylation; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Enzyme Activation; Exenatide; Female; Humans; Intercellular Adhesion Molecule-1; Matrix Metalloproteinase 9; Neoplasm Invasiveness; NF-kappa B; Ovarian Neoplasms; Phosphorylation; Signal Transduction; Sirtuin 1

Activation of autophagy suppresses ovarian cancer (OC). This in vitro study investigated whether the anti-tumour effect of exendin-4 against OC involves modulation of autophagy and figured out the possible mechanisms of action. SKOV-3 and OVCAR-3 cells (1 × 105/ml) were cultured in DMEM medium and treated with exendin-4 in the presence or absence of chloroquine (CQ), an autophagy inhibitor. In some cases, cells were also treated with exendin- 4 with or without pre-treatment with compound C (CC), an AMPK inhibitor, or insulin-like growth factor (IGF-1), a PI3K/Akt activator. Exendin-4 increased expression of beclin-1 and LC3I/II, suppressed expression of p62, reduced cell survival, migration, and invasion, and increased cell apoptosis and LDH release in both SKOV-3 and OVCAR-3 cells. Besides, exendin-4 reduced phosphorylation of mTORC1, 6SK, 4E-BP1, and Akt but increased phosphorylation of AMPK in both cell lines. These effects were associated with down-regulation of Bcl-2, suppression of nuclear phosphorylation of NF-κB p65, and increased expression of Bax and cleaved caspases 3/8. Chloroquine completely prevented the inhibitory effects of exendin-4 on the cell survival, Bcl-2, NF-κB, and cell invasiveness and abolished its stimulation of cell apoptosis and LDH release. Moreover, only the combined treatment with IGF-1 and CC completely abolished the observed effect of exendin-4 on the expression of beclin-1, LC3I/II, p62, as well as on cell survival, apoptosis, and LDH release. Exendin-4 exhibits a potent anti-tumour cytotoxic effect in SKOV-3 and OVCAR-3 cells by activating the markers of autophagy, mediated by activation of AMPK and inhibition of Akt.

Topics: AMP-Activated Protein Kinases; Apoptosis; Autophagy; Cell Line, Tumor; Exenatide; Female; Humans; Mechanistic Target of Rapamycin Complex 1; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

Glucagon-like peptide (GLP)-1 promotes proliferation and survival in β-cell; however, whether GLP-1 receptor agonists promote growth of human ovarian cancer cells remain unknown. We aimed to explore the effects of GLP-1 agents on ovarian cancer cells. GLP-1 receptor expression in human ovarian cancer tissues was detected by immunohistochemical analysis. The effects of exendin-4, a GLP-1R agonist, were investigated on proliferation, migration and invasion, apoptosis in vitro and tumor formation in nude mice of ovarian cancer cells. Our study demonstrated that GLP-1R expressed in both human ovarian cancer tissues and cell lines. Exendin-4 inhibited growth, migration and invasion and enhanced apoptosis of ovarian cancer cells through inhibition of the PI3K/Akt pathway. And exendin-4 attenuated tumor formation by ovarian cancer cells in vivo. Our study suggests that GLP-1R agonists do not promote the growth of ovarian cancer and may even have anticancer effect on selected diabetic patients with ovarian cancer.

Topics: Adult; Aged; Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Ovarian Neoplasms; Peptides; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Venoms