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Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma.
Int J Mol Sci. 2019 Jul 02; 20(13)IJ

Abstract

R428, a selective small molecule Axl inhibitor, is known to have anti-cancer effects, such as inhibition of invasion and proliferation and induction of cell death in cancer cells. The Axl receptor tyrosine kinase is highly expressed in cancer cells and the level of Axl expression is associated with survival, metastasis, and drug resistance of many cancer cells. However, the effect of Axl inhibition on overcoming anti-cancer drugs resistance is unclear. Therefore, we investigated the capability of Axl inhibition as a therapeutic agent for the induction of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) sensitivity. In this study, R428 markedly sensitized cancer cells to TRAIL-induced apoptotic cell death, but not in normal human skin fibroblast (HSF) and human umbilical vein cells (EA.hy926). Moreover, knockdown of Axl by siRNA also increased TRAIL-induced apoptosis. R428 decreased c-FLIP proteins levels via induction of miR-708 expression and survivin protein levels at the post-translational level, and we found that knockdown of Axl also decreased both c-FLIP and survivin protein expression. Overexpression of c-FLIP and survivin markedly inhibited R428 plus TRAIL-induced apoptosis. Furthermore, R428 sensitized cancer cells to multiple anti-cancer drugs-mediated cell death. Our results provide that inhibition of Axl could improve sensitivity to TRAIL through downregulation of c-FLIP and survivin expression in renal carcinoma cells. Taken together, Axl may be a tempting target to overcome TRAIL resistance.

Authors+Show Affiliations

Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea.Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea.Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea.Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea.Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia. Department of Experimental Carcinogenesis, Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia.Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea.Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Korea. kwontk@dsmc.or.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31269715

Citation

Woo, Seon Min, et al. "Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma." International Journal of Molecular Sciences, vol. 20, no. 13, 2019.
Woo SM, Min KJ, Seo SU, et al. Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma. Int J Mol Sci. 2019;20(13).
Woo, S. M., Min, K. J., Seo, S. U., Kim, S., Kubatka, P., Park, J. W., & Kwon, T. K. (2019). Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma. International Journal of Molecular Sciences, 20(13). https://doi.org/10.3390/ijms20133253
Woo SM, et al. Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma. Int J Mol Sci. 2019 Jul 2;20(13) PubMed PMID: 31269715.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma. AU - Woo,Seon Min, AU - Min,Kyoung-Jin, AU - Seo,Seung Un, AU - Kim,Shin, AU - Kubatka,Peter, AU - Park,Jong-Wook, AU - Kwon,Taeg Kyu, Y1 - 2019/07/02/ PY - 2019/06/11/received PY - 2019/06/29/revised PY - 2019/07/01/accepted PY - 2019/7/5/entrez PY - 2019/7/5/pubmed PY - 2020/1/7/medline KW - Axl KW - TRAIL KW - apoptosis KW - c-FLIP KW - survivin JF - International journal of molecular sciences JO - Int J Mol Sci VL - 20 IS - 13 N2 - R428, a selective small molecule Axl inhibitor, is known to have anti-cancer effects, such as inhibition of invasion and proliferation and induction of cell death in cancer cells. The Axl receptor tyrosine kinase is highly expressed in cancer cells and the level of Axl expression is associated with survival, metastasis, and drug resistance of many cancer cells. However, the effect of Axl inhibition on overcoming anti-cancer drugs resistance is unclear. Therefore, we investigated the capability of Axl inhibition as a therapeutic agent for the induction of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) sensitivity. In this study, R428 markedly sensitized cancer cells to TRAIL-induced apoptotic cell death, but not in normal human skin fibroblast (HSF) and human umbilical vein cells (EA.hy926). Moreover, knockdown of Axl by siRNA also increased TRAIL-induced apoptosis. R428 decreased c-FLIP proteins levels via induction of miR-708 expression and survivin protein levels at the post-translational level, and we found that knockdown of Axl also decreased both c-FLIP and survivin protein expression. Overexpression of c-FLIP and survivin markedly inhibited R428 plus TRAIL-induced apoptosis. Furthermore, R428 sensitized cancer cells to multiple anti-cancer drugs-mediated cell death. Our results provide that inhibition of Axl could improve sensitivity to TRAIL through downregulation of c-FLIP and survivin expression in renal carcinoma cells. Taken together, Axl may be a tempting target to overcome TRAIL resistance. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/31269715/Axl_Inhibitor_R428_Enhances_TRAIL_Mediated_Apoptosis_Through_Downregulation_of_c_FLIP_and_Survivin_Expression_in_Renal_Carcinoma_ L2 - http://www.mdpi.com/resolver?pii=ijms20133253 DB - PRIME DP - Unbound Medicine ER -