Multiple studies have shown that protein kinase Bβ (AKT2) is involved in the development and progression of ovarian cancer, however, its precise role remains unclear. Here we explored the underlying molecular mechanisms how AKT2 promotes ovarian cancer progression. We examined the effects of AKT2 in vitro in two ovarian cancer cell lines (SKOV3 and HEY), and in vivo by metastasis assay in nude mice. The migration and invasion ability of SKOV3 and HEY cells was determined by transwell assay. Overexpression and knockdown (with shRNA) experiments were carried out to unravel the underlying signaling mechanisms induced by AKT2. Overexpression of AKT2 led to increased expression of pyruvate kinase (PKM2) in ovarian cancer cells and in lung metastatic foci from nude mice. Elevated AKT2/PKM2 expression induced cell migration and invasion in vitro, as well as lung metastasis in vivo; silencing AKT2 blocked these effects. Meanwhile, PKM2 overexpression was unable to increase AKT2 expression. The expressions of p-PI3K, p-AKT2, and PKM2 were increased when stimulated by epidermal growth factor (EGF); however, these expressions were blocked when inhibited the PI3K by LY294002. STAT3 expression was elevated and NF-κB p65 nuclear translocation was activated both in vitro and in vivo when either AKT2 or PKM2 was overexpressed; and these effects were inhibited when silencing AKT2 expression. Taken together, AKT2 increases the migration and invasion of ovarian cancer cells in vitro and promotes lung metastasis in nude mice in vivo through PKM2-mediated elevation of STAT3 expression and NF-κB activation. In conclusion, we highlight a novel mechanism of the AKT2-PKM2-STAT3/NF-κB axis in the regulation of ovarian cancer progression, and our work suggested that both AKT2 and PKM2 may be potential targets for the treatment of ovarian cancer.

多项研究表明蛋白激酶Bβ（AKT2）参与卵巢癌的发生和发展，但其确切作用仍不清楚。在这里，我们探讨了 AKT2 促进卵巢癌进展的潜在分子机制。我们在体外检查了 AKT2 在两种卵巢癌细胞系（SKOV3 和 HEY）中的作用，并在体内通过裸鼠转移实验进行了检查。通过Transwell实验测定SKOV3和HEY细胞的迁移和侵袭能力。进行过表达和敲低（使用 shRNA）实验来揭示 AKT2 诱导的潜在信号传导机制。 AKT2 的过度表达导致卵巢癌细胞和裸鼠肺转移灶中丙酮酸激酶 (PKM2) 的表达增加。 AKT2/PKM2表达升高可诱导细胞体外迁移和侵袭，以及体内肺转移；沉默 AKT2 可以阻断这些效应。同时，PKM2 过表达无法增加 AKT2 表达。表皮生长因子（EGF）刺激后p-PI3K、p-AKT2和PKM2表达增加；然而，当 LY294002 抑制 PI3K 时，这些表达被阻断。当 AKT2 或 PKM2 过表达时，STAT3 表达升高，NF-κB p65 核转位在体外和体内均被激活；当 AKT2 表达沉默时，这些效应会受到抑制。综上所述，AKT2 通过 PKM2 介导的 STAT3 表达升高和 NF-κB 激活，在体外增加卵巢癌细胞的迁移和侵袭，并在体内促进裸鼠肺转移。 总之，我们强调了 AKT2-PKM2-STAT3/NF-κB 轴在调节卵巢癌进展中的新机制，我们的工作表明 AKT2 和 PKM2 可能是卵巢癌治疗的潜在靶点。