PIK3CA-mutated melanoma cells rely on cooperative signaling through mTORC1/2 for sustained proliferation.
PIK3CA-mutated melanoma cells rely on cooperative signaling through mTORC1/2 for sustained proliferation.
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DOI：
10.1111/pcmr.12586
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发表时间：
2017-05
影响因子：
4.3
通讯作者：
McMahon M
中科院分区：
文献类型：
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作者：
Silva JM;Deuker MM;Baguley BC;McMahon M
PI3‘-脂质信号可促进BRAF或NRAS突变的黑素细胞向黑色素瘤细胞的恶性转化。利用NRAS或BRAF突变的人黑色素瘤细胞共表达突变激活的PIK3CA，我们探索了PI3‘-脂质信号对细胞增殖的贡献。尽管PIK3CA具有突变活性，但黑色素瘤细胞对广谱PI3K抑制剂的生化和抗增殖作用比α选择性PI3K抑制剂更敏感。联合药理抑制MEK1/2和PI3K信号通路可产生更强的抗增殖作用和对细胞分裂周期的更大抑制作用，而不是单独抑制任何一条通路。对MEK1/2或PI3K下游信号通路的分析表明，这些通路通过mTORC1以AKT依赖的方式调节核糖体蛋白S6和4E-BP1的磷酸化，从而共同调控细胞的增殖。虽然抑制PI3K对移植瘤NRASQ61H/PIK3CAH1047R有细胞抑制作用，但联合抑制MEK1/2和PI3K可使黑色素瘤显著消退。这项研究提供了关于突变激活的PIK3CA如何与MEK1/2信号协同调节mTORC1/2以维持PIK3CA突变的黑色素瘤增殖的见解。
Malignant conversion of BRAF- or NRAS-mutated melanocytes into melanoma cells can be promoted by PI3’-lipid signaling. Using human NRAS- or BRAF-mutated melanoma cells that co-express mutationally activated PIK3CA, we explored the contribution of PI3′-lipid signaling to cell proliferation. Despite mutational activation of PIK3CA, melanoma cells were more sensitive to the biochemical and anti-proliferative effects of broader spectrum PI3K inhibitors than to an α-selective PI3K inhibitor. Combined pharmacological inhibition of MEK1/2 and PI3K signaling elicited more potent anti-proliferative effects and greater inhibition of the cell division cycle compared to single-agent inhibition of either pathway alone. Analysis of signaling downstream of MEK1/2 or PI3K revealed that these pathways cooperate to regulate cell proliferation through mTORC1-mediated effects on ribosomal protein S6 and 4E-BP1 phosphorylation in an AKT-dependent manner. Although PI3K inhibition resulted in cytostatic effects on xenografted NRASQ61H/PIK3CAH1047R melanoma, combined inhibition of MEK1/2 plus PI3K elicited significant melanoma regression. This study provides insights as to how mutationally activated PIK3CA acts in concert with MEK1/2 signaling to cooperatively regulate mTORC1/2 to sustain PIK3CA-mutated melanoma proliferation.