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首页> 外文期刊>Molecular Cancer >Activation of Akt pathway by transcription-independent mechanisms of retinoic acid promotes survival and invasion in lung cancer cells
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Activation of Akt pathway by transcription-independent mechanisms of retinoic acid promotes survival and invasion in lung cancer cells

机译：通过视黄酸的转录非依赖性机制激活Akt通路可促进肺癌细胞的存活和侵袭

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Background All- trans retinoic acid (ATRA) is currently being used in clinical trials for cancer treatment. The use of ATRA is limited because some cancers, such as lung cancer, show resistance to treatment. However, little is known about the molecular mechanisms that regulate resistance to ATRA treatment. Akt is a kinase that plays a key role in cell survival and cell invasion. Akt is often activated in lung cancer, suggesting its participation in resistance to chemotherapy. In this study, we explored the hypothesis that activation of the Akt pathway promotes resistance to ATRA treatment at the inhibition of cell survival and invasion in lung cancer. We aimed to provide guidelines for the proper use of ATRA in clinical trials and to elucidate basic biological mechanisms of resistance. Results We performed experiments using the A549 human lung adenocarcinoma cell line. We found that ATRA treatment promotes PI3k-Akt pathway activation through transcription-independent mechanisms. Interestingly, ATRA treatment induces the translocation of RARα to the plasma membrane, where it colocalizes with Akt. Immunoprecipitation assays showed that ATRA promotes Akt activation mediated by RARα -Akt interaction. Activation of the PI3k-Akt pathway by ATRA promotes invasion through Rac- GTPase , whereas pretreatment with 15e (PI3k inhibitor) or over-expression of the inactive form of Akt blocks ATRA-induced invasion. We also found that treatment with ATRA induces cell survival, which is inhibited by 15e or over-expression of an inactive form of Akt, through a subsequent increase in the levels of the active form of caspase-3. Finally, we showed that over-expression of the active form of Akt significantly decreases expression levels of the tumor suppressors RARβ2 and p53. In contrast, over-expression of the inactive form of Akt restores RARβ2 expression in cells treated with ATRA, indicating that activation of the PI3k-Akt pathway inhibits the expression of ATRA target genes. Conclusion Our results demonstrate that rapid activation of Akt blocks transcription-dependent mechanism of ATRA, promotes invasion and cell survival and confers resistance to retinoic acid treatment in lung cancer cells. These findings provide an incentive for the design and clinical testing of treatment regimens that combine ATRA and PI3k inhibitors for lung cancer treatment.
机译：背景技术全反式视黄酸（ATRA）目前正在临床试验中用于癌症治疗。 ATRA的使用受到限制，因为某些癌症（例如肺癌）显示出对治疗的抵抗力。然而，关于调节对ATRA治疗的抗性的分子机制知之甚少。 Akt是在细胞存活和细胞侵袭中起关键作用的激酶。 Akt在肺癌中经常被激活，表明它参与了对化学疗法的抵抗。在这项研究中，我们探讨了以下假设：Akt途径的激活在抑制细胞存活和侵袭中促进了对ATRA治疗的抗性。我们旨在为在临床试验中正确使用ATRA提供指导，并阐明耐药的基本生物学机制。结果我们使用A549人肺腺癌细胞系进行了实验。我们发现ATRA治疗通过转录独立机制促进PI3k-Akt途径的激活。有趣的是，ATRA处理诱导RARα移位到质膜，并与Akt共定位。免疫沉淀试验表明，ATRA促进RARα-Akt相互作用介导的Akt活化。 ATRA对PI3k-Akt途径的激活促进了Rac-GTPase的侵袭，而15e（PI3k抑制剂）的预处理或Akt非活性形式的过表达则阻止了ATRA诱导的侵袭。我们还发现，用ATRA进行治疗可诱导细胞存活，其通过随后增加caspase-3活性形式的水平来抑制15e或无活性形式的Akt的表达。最后，我们表明活性形式Akt的过表达显着降低了肿瘤抑制因子RARβ2和p53的表达水平。相反，无活性形式的Akt的过表达恢复了用ATRA处理的细胞中RARβ2的表达，表明PI3k-Akt途径的激活抑制了ATRA靶基因的表达。结论我们的结果表明，Akt的快速激活可阻断ATRA转录依赖性机制，促进其侵袭和细胞存活，并赋予肺癌细胞对视黄酸治疗的抗性。这些发现为结合ATRA和PI3k抑制剂治疗肺癌的治疗方案的设计和临床试验提供了动力。

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