This study investigated the effect of acylated synthetic ghrelin (AG) on the survival and proliferation of human chemosensitive ovarian cancer cells (A2780) and explored some mechanisms of action with a focus on the p53 apoptotic pathway and PI3K/Akt and NF-κB survival pathways. Human A2780 ovarian cancer cells were cultured with or without AG treatment in the presence or absence of cisplatin. In some cases, cisplatin+AG-treated cells were pre-incubated either with [D-Lys3]-GHRP-6, a ghrelin receptor antagonist, or with LY294002, a PI3K inhibitor. mRNA of ghrelin receptors(GHS-R1a and GHS-R1b), as well as, protein levels of GHS-R1a, were expressed abundantly in A2780 cells. AG treatment did not affect the mRNA and protein levels of GHS-R1a and GHS-R1b in both control and Cis-treated cells. However, while AG treatment had no effect on control cell viability, it significantly increased cell viability and proliferation and inhibited cell death in Cis-treated cells. In both control and Cis-treated cells, AG treatment significantly increased PI3K/Akt/mTOR signaling and enhanced the nuclear accumulation of NF-κB. Concomitantly, in both control and Cis-treated cells, AG significantly lowered the protein levels of p53, p-p53 (Ser16), PUMA, cytochrome C, and cleaved caspase-3. Interestingly, pre-incubating the cells with either [D-Lys3]-GHRP-6 or LY294002 completely abolished the above-mentioned effect of AG in both control and Cis-treated cells. In conclusion, the findings of this study show that AG promotes cell survival of the OC cells and renders them resistat to Cis therapy, an effect that is mediated by the activation of PI3K/Akt/mTOR and activation of NF-κB, and requires GHS-R1a.

中文翻译：

---

酰化的Ghrelin通过激活PI3K / Akt / mTOR存活途径使对顺铂化疗具有耐药性的卵巢癌细胞产生化学敏感性。

这项研究调查了酰化合成生长素释放肽（AG）对人化学敏感性卵巢癌细胞（A2780）存活和增殖的影响，并探讨了一些作用机制，重点研究了p53细胞凋亡途径以及PI3K / Akt和NF- κB生存途径。在有或没有顺铂的情况下，在有或没有AG处理的情况下培养人A2780卵巢癌细胞。在某些情况下，将顺铂+ AG处理的细胞与生长素释放肽受体拮抗剂[D-Lys3] -GHRP-6或PI3K抑制剂LY294002预孵育。ghrelin受体（GHS-R1a和GHS-R1b）的mRNA以及GHS-R1a的蛋白质水平在A2780细胞中大量表达。在对照和顺式处理的细胞中，AG处理均不影响GHS-R1a和GHS-R1b的mRNA和蛋白质水平。然而，尽管AG处理对控制细胞的存活率没有影响，但是它显着增加了细胞的存活率和增殖，并抑制了经顺式处理的细胞的细胞死亡。在对照和顺式处理的细胞中，κB。同时，在对照和顺式处理细胞中，AG均显着降低了p53，p-p53（Ser16），PUMA，细胞色素C和裂解的caspase-3的蛋白质水平。有趣的是，将细胞与[D-Lys3] -GHRP-6或LY294002一起预孵育完全消除了AG在对照和顺式处理细胞中的上述作用。总之，本研究结果显示的发现，即AG促进OC细胞的细胞存活和使它们resistat至C 18治疗，由PI3K / AKT / mTOR的激活和激活NF-介导的效果κ B，且需要GHS-R1a。