Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy; Department of Surgery 'P. Valdoni', Sapienza University of Rome, 00161, Rome, Italy.
Department of Experimental Medicine, Sapienza University of Rome, 00161, Rome, Italy; Department of Surgery 'P. Valdoni', Sapienza University of Rome, 00161, Rome, Italy.
Cancer Lett. 2021 Nov 1;520:48-56. doi: 10.1016/j.canlet.2021.07.001. Epub 2021 Jul 3.
The deregulation of PI3K/Akt signaling is among the most causes in inducing the acquisition of a metastatic phenotype in breast cancer cells, leading to Epithelial-Mesenchymal Transition (EMT). Inhibition of the PI3K/Akt pathway is known to be beneficial in the clinical setting. However, the activation of secondary pathways and toxicity profiles of available inhibitors, hindering optimal therapeutic results. Preliminary studies showed that myo-Inositol inhibits the PI3K/Akt pathway by exerting a pleiotropic anti-tumor action. Herein, we demonstrate that myo-Inositol triggers a prompt and profound remodeling of delineated expression pattern in triple-negative breast cancer cells (MDA-MB-231). Consequently, it inhibits metastasis and tumor progression through miR-125a-5p transcription and the subsequent inhibition of IPK1. In contrast, hormone-responsive breast cancer cells (MCF-7) are insensitive to myo-Inositol. This is due to the persistence of MDM2 synthesis promoted by estrogen-dependent pathways. Conversely, the counteraction of estrogen effects recovered the sensitivity to myo-Inositol in the hormone-responsive model. Overall, these results identify a novel axis primed by miR-125a-5p to downregulate IPK1 gene that inhibits metastasis. Thus, administration of myo-Inositol can activate this axis as a molecular target therapy in breast cancer.
PI3K/Akt 信号通路的失调是导致乳腺癌细胞获得转移表型的最常见原因之一，导致上皮-间充质转化（EMT）。抑制 PI3K/Akt 通路在临床环境中是有益的。然而，可用抑制剂的次级通路的激活和毒性特征，阻碍了最佳的治疗效果。初步研究表明，肌醇通过发挥多效性抗肿瘤作用来抑制 PI3K/Akt 通路。在此，我们证明肌醇触发三阴性乳腺癌细胞（MDA-MB-231）中明确表达模式的快速而深刻的重塑。因此，它通过 miR-125a-5p 的转录和随后抑制 IPK1 来抑制转移和肿瘤进展。相比之下，激素反应性乳腺癌细胞（MCF-7）对肌醇不敏感。这是由于雌激素依赖性途径促进的 MDM2 合成的持续存在。相反，雌激素作用的拮抗作用恢复了激素反应性模型对肌醇的敏感性。总的来说，这些结果确定了一个由 miR-125a-5p 启动的新轴，下调 IPK1 基因抑制转移。因此，肌醇的给药可以激活该轴作为乳腺癌的分子靶向治疗。
