scholarly journals Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance

2019 ◽  
Vol 21 (1) ◽  
pp. 237 ◽  
Author(s):  
Husain Yar Khan ◽  
James Ge ◽  
Misako Nagasaka ◽  
Amro Aboukameel ◽  
Gabriel Mpilla ◽  
...  

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.

2003 ◽  
Vol 1258 ◽  
pp. 157-161
Author(s):  
Alexei P Podtcheko ◽  
Satoshi Tsuda ◽  
Akira Ohtsuru ◽  
Vladimir A Saenko ◽  
Junichi KurebayashiI ◽  
...  

2003 ◽  
Vol 88 (4) ◽  
pp. 1889-1896 ◽  
Author(s):  
Alexei Podtcheko ◽  
Akira Ohtsuru ◽  
Satoshi Tsuda ◽  
Hirouki Namba ◽  
Vladimir Saenko ◽  
...  

2016 ◽  
Vol 35 (4) ◽  
pp. 2413-2418 ◽  
Author(s):  
LORENZO ALLEGRI ◽  
FEDERICA BALDAN ◽  
CATIA MIO ◽  
CINZIA PUPPIN ◽  
DIEGO RUSSO ◽  
...  

2012 ◽  
Vol 19 (5) ◽  
pp. 667-680 ◽  
Author(s):  
Muhammad Yasir Asghar ◽  
Tero Viitanen ◽  
Kati Kemppainen ◽  
Kid Törnquist

Anaplastic thyroid cancer (ATC) is the most aggressive form of human thyroid cancer, lacking any effective treatment. Sphingosine 1-phosphate (S1P) receptors and human ether-a′-go-go-related gene (HERG (KCNH2)) potassium channels are important modulators of cell migration. In this study, we have shown that the S1P1–3 receptors are expressed in C643 and THJ-16T human ATC cell lines, both at mRNA and protein level. S1P inhibited migration of these cells and of follicular FTC-133 thyroid cancer cells. Using the S1P1,3 inhibitor VPC-23019, the S1P2 inhibitor JTE-013, and the S1P2 receptor siRNA, we showed that the effect was mediated through S1P2. Treatment of the cells with the Rho inhibitor C3 transferase abolished the effect of S1P on migration. S1P attenuated Rac activity, and inhibiting Rac decreased migration. Sphingosine kinase inhibitor enhanced basal migration of cells, and addition of exogenous S1P inhibited migration. C643 cells expressed a nonconducting HERG protein, and S1P decreased HERG protein expression. The HERG blocker E-4031 decreased migration. Interestingly, downregulating HERG protein with siRNA decreased the basal migration. In experiments using HEK cells overexpressing HERG, we showed that S1P decreased channel protein expression and current and that S1P attenuated migration of the cells. We conclude that S1P attenuates migration of C643 ATC cells by activating S1P2 and the Rho pathway. The attenuated migration is also, in part, dependent on a S1P-induced decrease of HERG protein.


2007 ◽  
Vol 67 (14) ◽  
pp. 6956-6964 ◽  
Author(s):  
Nagako Akeno-Stuart ◽  
Michelle Croyle ◽  
Jeffrey A. Knauf ◽  
Roberta Malaguarnera ◽  
Donata Vitagliano ◽  
...  

2005 ◽  
Vol 90 (6) ◽  
pp. 3583-3591 ◽  
Author(s):  
Jingxuan Pan ◽  
Huizhi Huang ◽  
Lily Sun ◽  
Bingliang Fang ◽  
Sai-Ching Jim Yeung

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