LARP1, an RNA-binding protein, participates in ovarian cancer cell survival by regulating mitochondrial oxidative phosphorylation in response to the influence of the PI3K/mTOR pathway

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2024-12, Vol.1870 (8), p.167453, Article 167453
• Main Authors: Ma, Jiaoyan, Dong, Delu, Qi, Hang, Li, Jiaxin, Yu, Huimei, Hu, Xiaoqing, Sun, Liankun, Shen, Luyan
• Format: Article
• Language: English
• Subjects: Autoantigens - genetics; Autoantigens - metabolism; Cell Line, Tumor; Cell Survival; Female; Gene Expression Regulation, Neoplastic; Humans; LARP1; Mitochondria - metabolism; Mitochondrial; mRNA stability; Naphthyridines; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Oxidative Phosphorylation; OXPHOS; Phosphatidylinositol 3-Kinases - metabolism; PI3K/mTOR; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; Signal Transduction; SS-B Antigen; TOR Serine-Threonine Kinases - metabolism; Translation
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167453

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. [Display omitted] •This study highlights the significance of mitochondrial OXPHOS in regulating cell survival via the PI3K/mTOR pathway.•LARP1 regulates mRNA stability and translation of mitochondrial protein TFB2M, impacting mitochondrial function.•This study clarifies how the PI3K/mTOR pathway modulates ovarian cancer cells' response to treatment by regulating LARP1.