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通过荧光共振能量转移成像研究PI3K/mTOR与MEK联合抑制（SAR245409和匹马替尼）对黏液性卵巢癌细胞的协同抗肿瘤作用。

Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging.

作者信息

Inaba Kanako, Oda Katsutoshi, Aoki Kazuhiro, Sone Kenbun, Ikeda Yuji, Miyasaka Aki, Kashiyama Tomoko, Fukuda Tomohiko, Makii Chinami, Arimoto Takahide, Wada-Hiraike Osamu, Kawana Kei, Yano Tetsu, Osuga Yutaka, Fujii Tomoyuki

机构信息

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Imaging Platform for Spatio-Temporal Information, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

出版信息

Oncotarget. 2016 May 17;7(20):29577-91. doi: 10.18632/oncotarget.8807.

DOI:10.18632/oncotarget.8807
PMID:27102436
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5045418/
Abstract

The aim of this study was to clarify the synergistic effects of dual inhibition of the PI3K/mTOR and MAPK pathways in ovarian mucinous carcinoma (OMC) cells, using fluorescence resonance energy transfer (FRET) imaging. We exposed 6 OMC cell lines to a PI3K/mTOR inhibitor (voxtalisib, SAR245409) and/or a MEK inhibitor (pimasertib), and evaluated synergistic effects using the Chou-Talalay method. Then, S6K (PI3K pathway) and ERK (MAPK pathway) kinase activities, and their individual proliferative or cytotoxic effects were calculated by time-lapse FRET imaging. In combination with SAR245409, pimasertib (30 nM) synergistically inhibited cell growth (combination indexes: 0.03-0.5) and induced apoptosis in all 6 OMC cell lines. FRET-imaging results demonstrated that ERK inhibition induced both anti-proliferation and apoptosis in a dose-dependent manner in both MCAS and OAW42 cells. However, S6K inhibition suppressed proliferation in a threshold manner in both cell lines, although apoptosis was only induced in OAW42 cells. These results demonstrated that combined PI3K/mTOR and MEK inhibition exhibited synergistic antitumor effects in OMC cells and that FRET imaging is useful for analyzing kinase activities in live cells and elucidating their cytostatic and cytotoxic effects.

摘要

本研究的目的是利用荧光共振能量转移（FRET）成像，阐明PI3K/mTOR和MAPK信号通路双重抑制对卵巢黏液性癌（OMC）细胞的协同作用。我们将6种OMC细胞系暴露于PI3K/mTOR抑制剂（沃克替尼，SAR245409）和/或MEK抑制剂（匹美替尼），并使用Chou-Talalay方法评估协同作用。然后，通过延时FRET成像计算S6K（PI3K信号通路）和ERK（MAPK信号通路）激酶活性，以及它们各自的增殖或细胞毒性作用。与SAR245409联合使用时，匹美替尼（30 nM）在所有6种OMC细胞系中均协同抑制细胞生长（联合指数：0.03 - 0.5）并诱导细胞凋亡。FRET成像结果表明，ERK抑制在MCAS和OAW42细胞中均以剂量依赖的方式诱导抗增殖和细胞凋亡。然而，S6K抑制在两种细胞系中均以阈值方式抑制增殖，尽管仅在OAW42细胞中诱导了细胞凋亡。这些结果表明，联合抑制PI3K/mTOR和MEK在OMC细胞中表现出协同抗肿瘤作用，并且FRET成像可用于分析活细胞中的激酶活性并阐明其细胞生长抑制和细胞毒性作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/6152554cc69d/oncotarget-07-29577-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/f98027f3cb81/oncotarget-07-29577-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/7650add33e3f/oncotarget-07-29577-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/0289fe664284/oncotarget-07-29577-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/216a10b5d622/oncotarget-07-29577-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/497fe6947a36/oncotarget-07-29577-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/6152554cc69d/oncotarget-07-29577-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/f98027f3cb81/oncotarget-07-29577-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/7650add33e3f/oncotarget-07-29577-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/0289fe664284/oncotarget-07-29577-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/216a10b5d622/oncotarget-07-29577-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/497fe6947a36/oncotarget-07-29577-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a31/5045418/6152554cc69d/oncotarget-07-29577-g006.jpg

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