Tiwari Aadhya, Iida Mari, Kosnopfel Corinna, Abbariki Mahyar, Menegakis Apostolos, Fehrenbacher Birgit, Maier Julia, Schaller Martin, Brucker Sara Y, Wheeler Deric L, Harari Paul M, Rothbauer Ulrich, Schittek Birgit, Zips Daniel, Toulany Mahmoud
Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, 72076 Tuebingen, Germany.
Department of Radiation Oncology, University of Tuebingen, 72076 Tuebingen, Germany.
Cancers (Basel). 2020 Sep 29;12(10):2795. doi: 10.3390/cancers12102795.
The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in -mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus / mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in -mutated cells is mainly dependent on the MAPK/ERK pathway, while in /-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC.
多功能蛋白Y盒结合蛋白1（YB-1）可调节所有目前已描述的癌症标志，包括细胞增殖和存活。丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）和磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/Akt）信号通路也是参与细胞生长、增殖和存活的主要信号通路，且在人类癌症中经常过度激活。主要的功能获得性突变会导致MAPK信号通路的组成性激活，而PI3K/Akt信号通路的激活则通过磷酸酶和张力蛋白同源物（PTEN）缺失或PI3K催化亚基α的功能获得性突变发生。在本研究中，我们调查了在KRAS突变的三阴性乳腺癌（TNBC）MDA-MB-231细胞与PIK3CA/PTEN突变的TNBC MDA-MB-453细胞中，丝氨酸102（S102）位点YB-1磷酸化所涉及的潜在信号通路。我们的数据表明，KRAS突变细胞中YB-1的S102磷酸化主要依赖于MAPK/ERK信号通路，而在PIK3CA/PTEN突变细胞中，YB-1的S102磷酸化完全依赖于PI3K/Akt信号通路。独立于调节YB-1磷酸化的单个主导信号通路，双重靶向MEK和PI3K可有效抑制YB-1磷酸化并阻断细胞增殖。这代表了两条信号通路之间的功能性串扰。我们通过应用药理学抑制剂和基因方法从实验中获得的数据表明，YB-1是TNBC细胞通过MAPK和PI3K信号通路进行细胞增殖、克隆形成活性和肿瘤生长的关键因子。因此，双重抑制这两条信号通路或单一靶向YB-1可能是治疗TNBC的有效策略。
