a Department of Pharmacy , The First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi , China.
b Department of Pharmacy , The People's Hospital of Bayingol Mongolian Autonomous Prefecture , Korla , Xinjiang , China.
J Drug Target. 2018 Jan;26(1):27-35. doi: 10.1080/1061186X.2017.1332066. Epub 2017 Jun 14.
Multidrug resistance (MDR) is a serious obstacle in breast cancer patients which limits chemotherapeutic drugs application. Our previous study confirmed that overexpression of nucleophosmin (NPM) was closely related to MDR in methotrexate-resistant breast cancer cells (MCF-7/MTX), and NPM could be a potential therapeutic target for chemoresistance. In this work, we aim to investigate NPM-mediated resistance mechanism in breast carcinoma. The NPM level was strongly positive in breast carcinoma tissues compared with adjacent normal samples, which was associated with lymph node metastasis. We found abnormal expression of NPM activated PI3K/Akt pathway and affected downstream apoptosis factors. Then, NPM level was attenuated by RNA interfering technology, the sensitivity of MCF-7/MTX cells to methotrexate was obviously increased, factor level of mitochondria apoptosis pathway was significantly augmented, and Akt phosphorylation was inhibited. Furthermore, examination of Akt and NPM level demonstrated that Akt inhibitor MK-2206 sensitised resistant cells to methotrexate and induced MCF-7/MTX cell apoptosis by PI3K/Akt pathway and mitochondria apoptosis pathway. These suggested NPM-induced resistance and anti-apoptosis were required for Akt activity. NPM has a crucial function in MDR of breast cancer through influencing Akt activity and resistant cell apoptosis, and it could be expected to become a therapeutic target for chemoresistance in breast cancer.
多药耐药（MDR）是乳腺癌患者的严重障碍，限制了化疗药物的应用。我们之前的研究证实，核仁磷酸蛋白（NPM）的过表达与耐甲氨蝶呤乳腺癌细胞（MCF-7/MTX）中的多药耐药密切相关，NPM 可能是化学耐药性的潜在治疗靶点。在这项工作中，我们旨在研究 NPM 介导的乳腺癌耐药机制。NPM 水平在乳腺癌组织中明显高于相邻正常样本，与淋巴结转移有关。我们发现 NPM 的异常表达激活了 PI3K/Akt 通路，并影响了下游凋亡因子。然后，通过 RNA 干扰技术减弱 NPM 水平，MCF-7/MTX 细胞对甲氨蝶呤的敏感性明显增加，线粒体凋亡途径的因子水平显著增加，Akt 磷酸化受到抑制。此外，对 Akt 和 NPM 水平的检测表明，Akt 抑制剂 MK-2206 通过 PI3K/Akt 通路和线粒体凋亡通路使耐药细胞对甲氨蝶呤敏感，并诱导 MCF-7/MTX 细胞凋亡。这表明 Akt 活性需要 NPM 诱导的耐药性和抗凋亡作用。NPM 通过影响 Akt 活性和耐药细胞凋亡在乳腺癌的 MDR 中起着关键作用，有望成为乳腺癌化疗耐药的治疗靶点。
