Nuclear retention of Fbw7 by specific inhibitors of nuclear export leads to Notch1 degradation in pancreatic cancer
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Jiankun Gao1,2, Asfar S. Azmi3, Amro Aboukameel2, Michael Kauffman4, Sharon Shacham4, Abdul-Badi Abou-Samra5, and Ramzi M. Mohammad2,5
1 Sichuan College of Traditional Chinese Medicine, Mianyang, Sichuan, People’s Republic of China
2 Department of Oncology, Karmanos Cancer Institute, Detroit, Michigan, USA
3 Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA
4 Karyopharm Therapeutics, Natick MA, USA
5 Hamad Medical Corporation, Doha, Qatar
Ramzi M. Mohammad, email:
Keywords:Specific Inhibitors of Nuclear Export; Xpo1, Exportin 1, CRM1 inhibitor; Notch1; Fbw7; Apoptosis; Pancreatic Cancer
Received: January 8, 2014 Accepted:March 19, 2014 Published: March 21, 2014
Chromosome maintenance region 1 (CRM1) also called Exportin 1 (Xpo1), a protein found elevated in pancreatic ductal adenocarcinoma (PDAC), blocks tumor suppressor protein (TSP) function through constant nuclear export. Earlier we had shown that targeting CRM1 by our newly developed specific inhibitors of nuclear export (SINE) leads to inhibition of pancreatic cancer cell proliferation and tumor growth arrest. In this paper we define the mechanism of SINE action. Our lead SINE KPT-185 inhibits PDAC cell growth, cell migration, tumor invasion and induces apoptosis and G2-M cell cycle arrest in low nano molar range (IC50s~150 nM). Mechanistically we demonstrate that the activity of KPT-185 is associated with nuclear retention of Fbw7; which degrades nuclear Notch-1 leading to decreased tumor promoting markers such as C-Myc, Cyclin-D1, Hes1 and VEGF. The orally bioavailable SINE (KPT-251) showed potent anti-tumor activity in a Colo-357 PDAC xenografts model; residual tumor analysis showed activation of Fbw7 concomitant with attenuation of Notch1 and its downstream genes. These results suggest that the antitumor activity of KPT-185 is in part due to nuclear retention of Fbw7 and consequent Notch1 degradation. The new CRM1 inhibitors, therefore, hold strong potential and warrant further clinical investigations for PDAC.
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