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| Cancer letters. 2017 Jul 14. pii: S0304-3835(17)30435-4. doi: 10.1016/j.canlet.2017.07.009 |
| Sensitivity towards the GRP78 inhibitor KP1339/IT-139 is characterized by apoptosis induction via caspase 8 upon disruption of ER homeostasis. |
| Schoenhacker-Alte B1, Mohr T2, Pirker C3, Kryeziu K4, Kuhn PS5, Buck A6, Hofmann T7, Gerner C8, Hermann G9, Koellensperger G10, Keppler BK11, Berger W12, Heffeter P13 |
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Abstract The ruthenium drug and GRP78 inhibitor KP1339/IT-139 has already demonstrated promising anticancer activity in a phase I clinical trial. This study aimed to identify mechanisms underlying increased sensitivity to KP1339 treatment. Based on a screen utilizing 23 cell lines, a small panel was selected to compare KP1339-sensitive and low-responsive models. KP1339 sensitivity was neither based on differences in ruthenium accumulation, nor sensitivity to oxidative stress or constituents of KP1339 (ruthenium chloride and indazole). Subsequently, the biochemical response to KP1339 was analyzed using whole genome expression arrays indicating that, while sensitive cell lines were characterized by "response to chemical stimuli" and "regulation of cell death", low-responsive cells preferentially activated pathways controlling cell cycle, DNA repair, and metabolism. Cell culture experiments confirmed that, while low-responsive cells executed cell cycle arrest in G2 phase, pronounced apoptosis induction via activation of caspase 8 was found in sensitive cells. Cell death induction is based on a unique disruption of the ER homeostasis by depletion of key cellular chaperons including GRP78 in combination with enhanced KP1339-mediated protein damage. |
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Copyright © 2017 Elsevier B.V. All rights reserved. |
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KEYWORDS: GRP78, caspase 8, extrinsic pathway of programmed cell death, ruthenium, sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] |
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Publikations ID: 28716523 Quelle: öffnen |
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