Jin Hana, Kim Hye Jung
Department of Pharmacology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Korea.
Department of Convergence Medical Science (BK21 Plus), Gyeongsang National University, Jinju 52727, Korea.
Cancers (Basel). 2022 Aug 26;14(17):4124. doi: 10.3390/cancers14174124.
ESM-1, overexpressed in several cancer types, is a potential cancer diagnostic and prognostic indicator. In our previous study, we determined that RT-R-TNBC cells were more aggressive than TNBC cells, and this difference was associated with ESM-1 overexpression. However, the mechanism explaining upregulated ESM-1 expression in RT-R-TNBC cells compared to TNBC cells was unclear. Therefore, we aimed to identify the mechanism by which ESM-1 is overexpressed in RT-R-MDA-MB-231 cells. RT-R-MDA-MB-231 cells were treated with various ESM-1 transcription factor inhibitors, and only the FoxO1 inhibitor downregulated ESM-1 expression. FoxO1 nuclear localization was modulated by JNK and p38 MAPKs, which were differentially regulated by PKC, PDK1 and PAK1. PAK1 profoundly modulated JNK and p38 MAPKs, whereas PKC and PDK1 affected only p38 MAPK. P2YR activated by ATP, which is highly released from RT-R-BC cells, was involved in PAK1 activation, subsequent JNK and p38 MAPK activation, FoxO1 induction, and ESM-1 expression in RT-R-MDA-MB-231 cells. These findings suggest for the first time that ESM-1 was overexpressed in RT-R-MDA-MB-231 cells and regulated through the P2YR-PAK1-FoxO1 signaling pathway.
内皮细胞特异性分子-1（ESM-1）在多种癌症类型中过表达，是一种潜在的癌症诊断和预后指标。在我们之前的研究中，我们确定放疗抵抗的三阴乳腺癌（RT-R-TNBC）细胞比三阴乳腺癌（TNBC）细胞更具侵袭性，这种差异与ESM-1过表达有关。然而，与TNBC细胞相比，RT-R-TNBC细胞中ESM-1表达上调的机制尚不清楚。因此，我们旨在确定RT-R-MDA-MB-231细胞中ESM-1过表达的机制。用各种ESM-1转录因子抑制剂处理RT-R-MDA-MB-231细胞，只有FoxO1抑制剂下调了ESM-1的表达。FoxO1的核定位受JNK和p38丝裂原活化蛋白激酶（MAPKs）调节，而JNK和p38 MAPKs受蛋白激酶C（PKC）、丙酮酸脱氢酶激酶1（PDK1）和p21激活激酶1（PAK1）的差异调节。PAK1对JNK和p38 MAPKs有深刻的调节作用，而PKC和PDK1仅影响p38 MAPK。由RT-R-BC细胞大量释放的三磷酸腺苷（ATP）激活的P2Y受体（P2YR）参与了RT-R-MDA-MB-231细胞中PAK1的激活、随后的JNK和p38 MAPK激活、FoxO1诱导和ESM-1表达。这些发现首次表明，ESM-1在RT-R-MDA-MB-231细胞中过表达，并通过P2YR-PAK1-FoxO1信号通路调节。
