Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells.
Akt inhibitor augments anti-proliferative efficacy of a dual mTORC1/2 inhibitor by FOXO3a activation in p53 mutated hepatocarcinoma cells.
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DOI：
10.1038/s41419-021-04371-7
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发表时间：
2021-11-10
影响因子：
9
通讯作者：
Ray R
中科院分区：
文献类型：
--
作者：
Patra T;Meyer K;Ray RB;Kanda T;Ray R
肝细胞癌是最常见的恶性肿瘤相关死亡之一。肝细胞癌中P53基因突变与包括治疗局限性在内的不良临床病理特征有关。靶向治疗的组合可能有一些优势。AKT/mTOR信号通路参与调节细胞增殖和细胞死亡。AKT抑制剂(AZD5363)和mTORC1/2双重抑制剂(AZD8055)正在对肝癌和其他癌症进行临床试验。在这项研究中，我们研究了这些抑制剂是否成功地诱导了p53突变的肝癌细胞的抗增殖活性，及其潜在的机制。我们观察到，AZD5363和AZD8055联合治疗对p53突变或野生型肝癌细胞株具有协同的抗增殖活性，并诱导细胞凋亡。机制研究表明，AZD5363和AZD8055联合激活FOXO3a可诱导P53突变的肝癌细胞中Bim相关的凋亡，而保留功能性P53的细胞则增强Bax。SiRNA介导的Bim或Bax基因敲除可阻止经抑制剂处理的细胞的凋亡。我们进一步观察到，联合治疗抑制FOXO3a的磷酸化，并通过阻止Akt和SGK1的磷酸化来保护FOXO3a免受MDM2介导的降解。在此条件下，FOXO3a在细胞核中聚集，并在p53突变的肝癌细胞中诱导Bim转录。联合处理表达野生型P53的肝癌细胞会干扰FOXO3a功能，直接与功能P53相互作用，而不能诱导Bim相关的细胞死亡。另一方面，由于FOXO3a功能的不间断，在p53突变细胞中发生了Bim相关的细胞死亡。总体而言，我们的研究结果表明，双重mTORC1/2和Akt抑制剂的联合治疗方案可能是治疗携带p53突变的肝癌患者的有效策略。
Hepatocellular carcinoma (HCC) is one of the most common malignancy-related deaths. p53 mutation in HCC associates with worse clinicopathologic features including therapeutic limitation. A combination of targeted therapy may have some advantages. Akt/mTOR signaling contributes to the regulation of cell proliferation and cell death. Akt inhibitor (AZD5363) and mTORC1/2 dual inhibitor (AZD8055) are in a clinical trial for HCC and other cancers. In this study, we examined whether these inhibitors successfully induce antiproliferative activity in p53 mutant HCC cells, and the underlying mechanisms. We observed that a combination of AZD5363 and AZD8055 treatment synergizes antiproliferative activity on p53 mutated or wild-type HCC cell lines and induces apoptotic cell death. Mechanistic insights indicate that a combination of AZD5363 and AZD8055 activated FOXO3a to induce Bim-associated apoptosis in p53 mutated HCC cells, whereas cells retaining functional p53 enhanced Bax. siRNA-mediated knock-down of Bim or Bax prevented apoptosis in inhibitor-treated cells. We further observed a combination of treatment inhibits phosphorylation of FOXO3a and protects FOXO3a from MDM2 mediated degradation by preventing the phosphorylation of Akt and SGK1. FOXO3a accumulates in the nucleus under these conditions and induces Bim transcription in p53 mutant HCC cells. Combination treatment in the HCC cells expressing wild-type p53 causes interference of FOXO3a function for direct interaction with functional p53 and unable to induce Bim-associated cell death. On the other hand, Bim-associated cell death occurs in p53 mutant cells due to uninterrupted FOXO3a function. Overall, our findings suggested that a combined regimen of dual mTORC1/2 and Akt inhibitors may be an effective therapeutic strategy for HCC patients harboring p53 mutation.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
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作者：
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作者：
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作者：
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通讯作者：
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影响因子：
5.3
作者：
Brunet, A;Park, J;Greenberg, ME
通讯作者：
Greenberg, ME