靶向 PI3K/mTOR 通路并调节线粒体适应预计将成为癌症治疗的关键方法。尽管PI3K/mTOR通路对线粒体的调节已被研究，但由于其调节机制的复杂性，人们对其了解还不够透彻。 RNA结合蛋白（RBP）通过转录后调节选择性地调节基因表达，在癌症进展中发挥关键作用。 LARP1 是 mTOR 通路的下游 RBP，参与线粒体介导的 BCL-2 细胞存活。因此，探索LARP1参与卵巢癌细胞中PI3K/mTOR介导的线粒体相关蛋白的翻译调节可能有助于阐明线粒体在PI3K/mTOR通路中的作用。我们发现，与SKOV3细胞不同，A2780细胞的线粒体功能未受影响，对PI3K/mTOR双重抑制剂PKI-402不敏感，这表明细胞存活可能与线粒体功能有关。 PKI-402 处理后 LARP1 基因的敲低导致 A2780 细胞中线粒体功能受损，这可能是由于线粒体转录起始因子 TFB2M 和呼吸链复合物 II 亚基 SDHB 的 mRNA 稳定性降低和蛋白质翻译减少所致。 LARP1通过与TFB2M mRNA结合、调节线粒体DNA编码基因或间接调节核DNA编码SDHB基因来影响蛋白质翻译，最终干扰线粒体氧化磷酸化并导致细胞凋亡。因此，LARP1可能是PI3K/mTOR通路中调节mRNA翻译和线粒体功能的重要介质。靶向 mTOR 通路下游的 RBP（例如 LARP1）可能为卵巢癌治疗提供新的见解和潜在的治疗方法。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Targeting the PI3K/mTOR pathway and modulating mitochondrial adaptation is expected to be a critical approach for cancer therapy. Although the regulation of mitochondria by the PI3K/mTOR pathway has been investigated, it is not well understood due to the complexity of its regulatory mechanisms. RNA-binding proteins (RBPs) selectively regulate gene expression through post-transcriptional modulation, playing a key role in cancer progression. LARP1, a downstream RBP of the mTOR pathway, is involved in mitochondria-mediated BCL-2 cell survival. Therefore, exploring the involvement of LARP1 in PI3K/mTOR-mediated translational regulation of mitochondria-associated proteins in ovarian cancer cells could help elucidate the role of mitochondria in the PI3K/mTOR pathway. We found that, unlike SKOV3 cells, the mitochondrial function of A2780 cells was not affected, which were insensitive to the dual PI3K/mTOR inhibitor PKI-402, suggesting that cell survival may be related to mitochondrial function. Knockdown of the LARP1 gene after PKI-402 treatment resulted in impaired mitochondrial function in A2780 cells, possibly due to decreased mRNA stability and reduced protein translation of the mitochondrial transcription initiation factor, TFB2M, and the respiratory chain complex II subunit, SDHB. LARP1 affects protein translation by binding to TFB2M mRNA, regulating mitochondrial DNA-encoded genes, or indirectly regulating the nuclear DNA-encoded SDHB gene, ultimately interfering with mitochondrial oxidative phosphorylation and leading to apoptosis. Therefore, LARP1 may be an important mediator in the PI3K/mTOR pathway for regulating mRNA translation and mitochondrial function. Targeting RBPs such as LARP1 downstream of the mTOR pathway may provide new insights and potential therapeutic approaches for ovarian cancer treatment.Copyright © 2024 Elsevier B.V. All rights reserved.