Abstract：
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.
摘要：
靶向PI3K/mTOR通路和调节线粒体适应有望成为癌症治疗的关键方法。尽管已经研究了PI3K/mTOR通路对线粒体的调节，由于其监管机制的复杂性，它还没有得到很好的理解。RNA结合蛋白（RBP）通过转录后调节选择性调节基因表达，在癌症进展中发挥关键作用。LARP1，mTOR通路的下游RBP，参与线粒体介导的BCL-2细胞存活。因此,探讨LARP1参与PI3K/mTOR介导的卵巢癌细胞线粒体相关蛋白的翻译调控,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细胞的线粒体功能没有受到影响，对双PI3K/mTOR抑制剂PKI-402不敏感，提示细胞存活可能与线粒体功能有关。PKI-402处理后敲除LARP1基因导致A2780细胞线粒体功能受损,可能是由于线粒体转录起始因子的mRNA稳定性降低和蛋白质翻译减少，TFB2M,和呼吸链复合物II亚基，SDHB。LARP1通过与TFB2MmRNA结合影响蛋白质翻译，调节线粒体DNA编码的基因，或间接调节核DNA编码的SDHB基因，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RBP如mTOR通路下游的LARP1可能为卵巢癌治疗提供新的见解和潜在的治疗方法。
