State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Bioorganic and Medicinal Chemistry Research Center, School of Pharmaceutical Sciences, Wenzhou Medical College, Wenzhou 325035, China.
Cell Death Dis. 2017 Sep 14;8(9):e3049. doi: 10.1038/cddis.2017.444.
Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor prognosis owing to the high propensity for metastatic progression and the absence of specific targeted treatment. Here, we revealed that small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) exhibited potent anti-cancer activity on all TNBC cells tested. Apart from apoptosis induction, RL71 triggered excessive autophagic cell death, the main contributor to RL71-induced TNBC cell death. RL71 augmented the release of Ca from the endoplasmic reticulum (ER) into the cytosol by inhibiting SERCA2 activity. The disruption of calcium homeostasis induced ER stress, leading to apoptosis. More importantly, the elevated intracellular calcium signals induced autophagy through the activation of the CaMKK-AMPK-mTOR pathway and mitochondrial damage. In two TNBC xenograft mouse models, RL71 also displayed strong efficacy including the inhibition of tumor growth, the reduction of metastasis, as well as the prolongation of survival time. These findings suggest SERCA2 as a previous unknown target candidate for TNBC treatment and support the idea that autophagy inducers could be useful as new therapeutics in TNBC treatment.
三阴性乳腺癌（TNBC）具有侵袭性表型和不良预后，这归因于转移性进展的高倾向和缺乏特异性靶向治疗。在这里，我们揭示了小分子 RL71 靶向肌浆/内质网钙 ATP 酶 2（SERCA2），对所有测试的 TNBC 细胞均表现出强大的抗癌活性。除了诱导细胞凋亡外，RL71 还引发过度的自噬细胞死亡，这是 RL71 诱导 TNBC 细胞死亡的主要原因。RL71 通过抑制 SERCA2 活性，增加内质网（ER）中钙向细胞质的释放。钙稳态的破坏诱导内质网应激，导致细胞凋亡。更重要的是，升高的细胞内钙信号通过激活 CaMKK-AMPK-mTOR 通路和线粒体损伤诱导自噬。在两种 TNBC 异种移植小鼠模型中，RL71 也表现出强大的疗效，包括抑制肿瘤生长、减少转移以及延长生存时间。这些发现表明 SERCA2 是 TNBC 治疗中以前未知的靶标候选物，并支持自噬诱导剂可作为 TNBC 治疗的新疗法的观点。
