Exendin‐4 exhibits a tumour suppressor effect in SKOVR‐3 and OVACR‐3 ovarian cancer cells lines by the activation of SIRT1 and inhibition of NF‐κB

Abstract

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.

Antiproliferative Ruthenium Complexes Containing Curcuminoid Ligands Tested In Vitro on Human Ovarian Tumor Cell Line A2780, towards Their Capability to Modulate the NF-κBTranscription Factor, FGF-2 Growth Factor, and MMP-9 Pathway

“…MMP-9 is involved in ovarian cancer progression, metastasis, and platinum-drug resistance [ 48 ], and MMP-9 inhibition can improve the standard anticancer treatment efficacy. Acting on the MMP-9 pathway, NF- κ B mediated signaling can be initiated for tumor suppression [ 49 ].…”

Anticancer and Apoptotic Activity in Cervical Adenocarcinoma HeLa Using Crude Extract of Ganoderma applanatum

“…Accordingly, ubiquitin-proteasome inhibitors of any step inhibit NFκB activation by stabilizing IκB [27]. IKK protein is phosphorylated at two serine residues (Ser176/180 of IKKα or Ser 177/181 of IKKβ) and subsequently induces the phosphorylation of IκBα at Ser 32/36 [28]. Significantly inhibiting the phosphorylation of p-IKKα (Ser176/180) and p-IκBα (Ser32) then leads to a decrease in nuclear levels of NFκB p65 [28].…”

“…IKK protein is phosphorylated at two serine residues (Ser176/180 of IKKα or Ser 177/181 of IKKβ) and subsequently induces the phosphorylation of IκBα at Ser 32/36 [28]. Significantly inhibiting the phosphorylation of p-IKKα (Ser176/180) and p-IκBα (Ser32) then leads to a decrease in nuclear levels of NFκB p65 [28]. Various anticancer drugs have shown anti-NFκB activity, which may be related to their anti-tumor effects, possibly by reducing NFκBs proliferative and antiapoptotic activity [29].…”

<p>Inactivation of Pancreatic Stellate Cells by Exendin-4 Inhibits the Migration and Invasion of Pancreatic Cancer Cells</p>

“…Previous reports have shown that exendin-4 inhibits NF-κB activation in ovarian and breast cancer cells, thus inducing cell death and suppression of migration and invasion. 19,24 As a downstream cytokine of NF-κB signaling, SDF-1 and its receptor CXCR4 play an important role in pancreatic cancer progression. Our previous study showed that SDF-1 is predominantly expressed in PSCs, and its upregulation in PSCs increases the invasion of pancreatic cancer cells.…”

“…Given that exendin-4 inhibits NF-κB activation in several cancer cells, 19,24 we measured the levels of p65 and phospho-p65 (p-p65) in PSCs with or without exendin-4 treatment. As shown in Figure 2A and B, exendin-4 suppressed the expression of p-p65 and p-IκBα and enhanced that of IκBα.…”