Crosstalk between PI3K and Ras pathways via protein phosphatase 2A in human ovarian clear cell carcinoma.
Crosstalk between PI3K and Ras pathways via protein phosphatase 2A in human ovarian clear cell carcinoma.
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DOI：
10.1080/15384047.2014.1002362
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发表时间：
2015
影响因子：
3.6
通讯作者：
Asahi M
中科院分区：
文献类型：
--
作者：
Takai M;Nakagawa T;Tanabe A;Terai Y;Ohmichi M;Asahi M
缺氧诱导因子-1 （HIF-1）是包括卵巢癌在内的所有类型癌症最有前途的药理学靶点之一。卵巢透明细胞癌（OCCC）对化疗不敏感，预后较差。为了阐明这种令人困扰的癌症的特点，我们检测了各种卵巢癌细胞系在常氧或缺氧条件下HIF-1α的表达。HIF-1α在常氧条件下仅在OCCC细胞系RMG-1中高表达。为了研究HIF-1是否参与了RMG-1细胞的肿瘤发生，我们建立了HIF-1α-沉默细胞RMG-1HKD。RMG-1HKD细胞的增殖速度比RMG-1细胞快。此外，RMG-1HKD细胞中Ras通路的MEK/ERK活性增加，而PI3K通路的mTOR活性没有变化。Ras通路的激活是由于PP2A失活导致磷酸化的MEK增加。为了确认体内PI3K和Ras通路之间的串扰，我们将RMG-1或RMG-1HKD细胞用雷帕霉素（mTOR抑制剂）、PD98059 （MEK抑制剂）或两者同时移植到裸鼠皮肤中。RMG-1HKD细胞对PD98059的敏感性高于RMD-1细胞，而联合治疗对两种细胞产生协同抑制。这些发现表明，抑制HIF-1 （PI3K通路中mTOR的下游靶点）通过PP2A失活导致MEK磷酸化增加，从而激活Ras通路，这两条通路之间的串扰可以应用于联合治疗HIF-1过表达的癌症，如OCCC。
Hypoxia-inducible factor-1 (HIF-1) is one of the most promising pharmacological targets for all types of cancer, including ovarian cancer. Ovarian clear cell carcinoma (OCCC) has poor prognosis because of its insensitivity to chemotherapy. To elucidate the characteristics of this troublesome cancer, we examined HIF-1α expression under normoxia or hypoxia in various ovarian cancer cell lines. HIF-1α was highly expressed under normoxia only in RMG-1, an OCCC cell line. To examine whether HIF-1 is involved in the tumorigenesis of RMG-1 cells, we established HIF-1α-silenced cells, RMG-1HKD. The proliferation rate of RMG-1HKD cells was faster than that of RMG-1 cells. Furthermore, the activity of MEK/ERK in the Ras pathway increased in RMG-1HKD cells, whereas that of mTOR in the PI3K pathway did not change. Activation of the Ras pathway was attributable to the increase in phosphorylated MEK via PP2A inactivation. To confirm the crosstalk between the PI3K and Ras pathways in vivo, RMG-1 or RMG-1HKD cells were transplanted into the skin of nude mice with rapamycin (an inhibitor of mTOR), PD98059 (an inhibitor of MEK), or both. RMG-1HKD cells showed higher sensitivity to PD98059 than that observed in RMD-1 cells, whereas the combination therapy resulted in synergistic inhibition of both cells. These findings suggest that inhibition of HIF-1, a downstream target of mTOR in the PI3K pathway, activates the Ras pathway on account of the increase in MEK phosphorylation via PP2A inactivation, and the crosstalk between the 2 pathways could be applied in the combination therapy for HIF-1-overexpressing cancers such as OCCC.