Key Laboratory of Biotechnology of Antibiotics of National Health and Family Planning Commission (NHFPC), Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050, China.
China Astronaut Research and Training Centre, Beijing, 100094, China.
Acta Pharmacol Sin. 2018 Aug;39(8):1347-1358. doi: 10.1038/aps.2017.171. Epub 2017 Dec 28.
c-Myc, a key activator of cell proliferation and angiogenesis, promotes the development and progression of breast cancer. Ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) is a multifunctional scaffold protein that suppresses the proliferation of breast cancer cells. In this study we investigated whether the cancer-suppressing effects of EBP50 resulted from its regulation of c-Myc signaling in human breast cancer MCF-7 cells in vitro and in vivo. We first found a significant correlation between EBP50 and c-Myc expression levels in breast cancer tissue, and demonstrated that EBP50 suppressed cell proliferation through decreasing the expression of c-Myc and its downstream proteins cyclin A, E and Cdc25A in MCF-7 cells. We further showed that EBP50 did not regulate c-Myc mRNA expression, but it promoted the degradation of c-Myc through the autophagic lysosomal pathway. Moreover, EBP50 promoted integration between c-Myc and p62, an autophagic cargo protein, triggering the autophagic lysosomal degradation of c-Myc. In EBP50-silenced MCF-7 cells, activation of autophagy by Beclin-1 promoted the degradation of c-Myc and inhibited cell proliferation. These results demonstrate that the EBP50/Beclin-1/p62/c-Myc signaling pathway plays a role in the proliferation in MCF-7 breast cancer cells: EBP50 stimulates the autophagic lysosomal degradation of c-Myc, thereby inhibits the proliferation of MCF-7 cells. Based on our results, promoting the lysosomal degradation of c-Myc might be a promising new strategy for treating breast cancer.
c-Myc 是细胞增殖和血管生成的关键激活因子，促进乳腺癌的发展和进展。Ezrin-radixin-moesin 结合磷蛋白 50（EBP50）是一种多功能支架蛋白，可抑制乳腺癌细胞的增殖。在这项研究中，我们研究了 EBP50 是否通过调节体外和体内人乳腺癌 MCF-7 细胞中的 c-Myc 信号来抑制癌症。我们首先发现 EBP50 与乳腺癌组织中 c-Myc 表达水平之间存在显著相关性，并证明 EBP50 通过降低 MCF-7 细胞中 c-Myc 及其下游蛋白 cyclin A、E 和 Cdc25A 的表达来抑制细胞增殖。我们进一步表明，EBP50 不调节 c-Myc mRNA 表达，但通过自噬溶酶体途径促进 c-Myc 的降解。此外，EBP50 促进 c-Myc 与自噬货物蛋白 p62 之间的结合，触发 c-Myc 的自噬溶酶体降解。在 EBP50 沉默的 MCF-7 细胞中，Beclin-1 激活自噬促进了 c-Myc 的降解并抑制了细胞增殖。这些结果表明，EBP50/Beclin-1/p62/c-Myc 信号通路在 MCF-7 乳腺癌细胞的增殖中起作用：EBP50 刺激 c-Myc 的自噬溶酶体降解，从而抑制 MCF-7 细胞的增殖。基于我们的结果，促进 c-Myc 的溶酶体降解可能是治疗乳腺癌的一种有前途的新策略。
