Department of Cell Biology, Key Laboratory of Cell Biology of National Health Commission of the PRC, Key Laboratory of Medical Cell Biology of Ministry of Education of the PRC, China Medical University, No.77, Puhe Road, Shenyang, 110122, Liaoning, China.
Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China.
Int J Biol Sci. 2021 Mar 27;17(5):1315-1327. doi: 10.7150/ijbs.58102. eCollection 2021.
Although p21 activated kinase 5 (PAK5) is related to the progression of multiple cancers, its biological function in breast cancer remains unclear. Apoptosis-inducing factor (AIF) is a vital apoptosis factor in mitochondria, which can be released from mitochondria and enter the nucleus, causing caspase-independent apoptosis. In this study, we reveal that PAK5 inhibits apoptosis by preventing the nuclear translocation of AIF. PAK5 inhibits the release of AIF from mitochondria in breast cancer cells by decreasing the mitochondria membrane permeability and increasing the membrane potential. Furthermore, PAK5 phosphorylates AIF at Thr281 site to inhibit the formation of AIF/importin α3 complex, leading to decrease AIF nuclear translocation. Functionally, we demonstrate that PAK5-mediated AIF phosphorylation promotes the proliferation of breast cancer cells and accelerates the growth of breast cancer . Significantly, PAK5 and AIF expression in breast cancer are positively correlated with poor patient prognosis. PAK5 expression is negatively correlated with AIF nuclear translocation. These results suggest that PAK5-AIF signaling pathway may play an essential role in mammary tumorigenesis, providing a new therapeutic target for the treatment of breast cancer.
虽然 p21 激活激酶 5（PAK5）与多种癌症的进展有关，但它在乳腺癌中的生物学功能仍不清楚。凋亡诱导因子（AIF）是线粒体中一种重要的凋亡因子，可从线粒体释放并进入细胞核，引起 Caspase 非依赖性凋亡。在本研究中，我们揭示了 PAK5 通过阻止 AIF 的核易位来抑制细胞凋亡。PAK5 通过降低线粒体膜通透性和增加膜电位来抑制乳腺癌细胞中线粒体 AIF 的释放。此外，PAK5 在 Thr281 位点磷酸化 AIF，抑制 AIF/importin α3 复合物的形成，从而减少 AIF 的核易位。功能上，我们证明 PAK5 介导的 AIF 磷酸化促进了乳腺癌细胞的增殖，并加速了乳腺癌的生长。重要的是，乳腺癌中 PAK5 和 AIF 的表达与患者预后不良呈正相关。PAK5 表达与 AIF 的核易位呈负相关。这些结果表明，PAK5-AIF 信号通路可能在乳腺肿瘤发生中发挥重要作用，为乳腺癌的治疗提供了新的治疗靶点。
