Sajadimajd Soraya, Yazdanparast Razieh
Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran.
Apoptosis. 2017 Jan;22(1):135-144. doi: 10.1007/s10495-016-1291-9.
Trastuzumab (Herceptin) monoclonal antibody directed against HER2 receptor has been administered as a treatment for metastatic HER2 positive breast cancer. The problematic issue in treatment of HER2 positive breast cancer cells is commonly the induction of resistance to trastuzumab which might be due to modulation of some vital signaling elements such as Notch1 and Pin1. In this study, we were aimed to investigate whether the cross talk between pin1 and Notch1 has a role in this event. Our results indicated that the expression level of Pin1 in resistant SKBR3 cells increased by about twofold relative to sensitive SKBR3 cells. Besides, Pin1 inhibition via juglone reduced the extent of proliferation, colony formation and migration capacity of resistant SKBR3 cells. In addition, despite a feed forward loop between Notch1 and Pin1 in sensitive SKBR3 cells, inhibition of Notch1 cleavage in resistant SKBR3 cells did not affect pin1 level whereas pin1 inhibition by juglone reduced the level of Hes1, p-Akt and increased the cellular content of Numb. Therefore, we concluded that pin1 inhibition could be considered as a promising sensitizing strategy to weaken trastuzumab resistance.
针对HER2受体的曲妥珠单抗（赫赛汀）单克隆抗体已被用于治疗转移性HER2阳性乳腺癌。治疗HER2阳性乳腺癌细胞时的一个问题通常是对曲妥珠单抗产生耐药性，这可能是由于某些重要信号元件（如Notch1和Pin1）的调节所致。在本研究中，我们旨在探究Pin1和Notch1之间的相互作用是否在此过程中发挥作用。我们的结果表明，与敏感的SKBR3细胞相比，耐药的SKBR3细胞中Pin1的表达水平增加了约两倍。此外，胡桃醌抑制Pin1可降低耐药SKBR3细胞的增殖程度、集落形成能力和迁移能力。此外，尽管在敏感的SKBR3细胞中Notch1和Pin1之间存在前馈环，但抑制耐药SKBR3细胞中的Notch1切割并不影响Pin1水平，而胡桃醌抑制Pin1则降低了Hes1、p-Akt的水平并增加了Numb的细胞含量。因此，我们得出结论，抑制Pin1可被视为一种有前景的增敏策略，以减弱曲妥珠单抗耐药性。
