Mechanistic insights into cancer drug resistance through optogenetic PI3K signaling hyperactivation
Mechanistic insights into cancer drug resistance through optogenetic PI3K signaling hyperactivation
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DOI：
10.1016/j.chembiol.2022.10.002
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发表时间：
2022-11-17
影响因子：
8.6
通讯作者：
Ozawa, Takeaki
中科院分区：
文献类型：
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作者：
Ueda, Yoshibumi;Miura, Yuri;Ozawa, Takeaki
磷脂酰肌醇3-激酶（PI 3 K）信号传导的过度活化是癌细胞中的突出特征。然而，这种状态下的恶性行为的机制仍然未知。在这里，我们描述了通过蛋白质合成途径，PI 3 K信号下游的癌症耐药机制。开发了控制PI 3 K信号传导的光遗传学工具（命名为PPAP 2）。稳定表达PPAP 2的黑色素瘤细胞（A375-PPAP 2）在超活化状态下获得对癌症药物的抗性。蛋白质组分析显示，抗凋亡因子肿瘤坏死因子α诱导蛋白8（TNFAIP 8）的表达上调。TNFAIP 8上调是由先前存在的mRNA的蛋白质翻译介导的。这些结果表明，癌细胞通过从预先存在的mRNA上调TNFAIP 8表达而逃避死亡，即使烷化剂损伤DNA。
Hyperactivation of phosphatidylinositol 3-kinase (PI3K) signaling is a prominent feature in cancer cells. How-ever, the mechanism underlying malignant behaviors in the state remains unknown. Here, we describe a mechanism of cancer drug resistance through the protein synthesis pathway, downstream of PI3K signaling. An optogenetic tool (named PPAP2) controlling PI3K signaling was developed. Melanoma cells stably ex-pressing PPAP2 (A375-PPAP2) acquired resistance to a cancer drug in the hyperactivation state. Proteome analyses revealed that expression of the antiapoptotic factor tumor necrosis factor alpha-induced protein 8 (TNFAIP8) was upregulated. TNFAIP8 upregulation was mediated by protein translation from preexisting mRNA. These results suggest that cancer cells escape death via upregulation of TNFAIP8 expression from preexisting mRNA even though alkylating cancer drugs damage DNA.