Abstract 4309: Mode of action of LTX315-induced cell death
| العنوان: | Abstract 4309: Mode of action of LTX315-induced cell death |
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| المؤلفون: | Sabrina Forveille, Guido Kroemer, Oliver Kepp, Allan Sauvat, Sylvère Durand, Heng Zhou, Takahiro Yamazaki, Valentina Sica, Sylvie Souquere, Øystein Rekdal |
| المصدر: | Cancer Research. 77:4309-4309 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Cancer Research, Programmed cell death, biology, Chemistry, Mitochondrion, Cell biology, Cell killing, Oncology, Apoptosis, Cancer cell, biology.protein, Immunogenic cell death, Secretion, Caspase |
| الوصف: | The experimental anticancer agent LTX-315 is an amphipathic cationic peptide that efficiently eradicates cancer cells in vitro and in vivo. Attracted by its efficacy we launched an in depth mechanistic study on LTX-315. First we focused on the mode of action of LTX-315 and found that the agent failed to induce morphological signs of apoptosis but evoked necrotic phenotypes. Accordingly, LTX-315 failed to stimulate the activation of caspases, and the pan-caspase inhibitor Z-VAD-fmk was unable to reduce cell killing. We then studied its subcellular localization by fractionation of LTX-315-treated cells, and revealed that the agent was enriched in mitochondria and caused an immediate arrest of mitochondrial respiration without any major uncoupling effect. LTX-315 disrupted the mitochondrial network, dissipated the mitochondrial inner transmembrane potential, and caused the release of mitochondrial intermembrane proteins into the cytosol. Cells lacking the two pro-death multidomain proteins BAX and BAK, were less susceptible to LTX-315-mediated killing. Moreover, cells engineered to lose their mitochondria were resistant against LTX-315, underscoring the importance of this organelle for LTX-315-mediated cytotoxicity. Further, we observed that LTX-315 induced all known characteristics of immunogenic cell death, including calreticulin exposure, ATP secretion, HMGB1 exodus and type-1 interferon induction. When injected into established cancers, LTX-315 caused a transiently hemorrhagic focal necrosis that was accompanied by massive release of HMGB1 (from close-to-all cancer cells), as well caspase-3 activation in a fraction of the cells. Collectively, these results support the idea that LTX-315 triggers unregulated necrosis, and kills cancer cells by virtue of its capacity to permeabilize mitochondrial membranes. In addition, LTX-315 can induce ICD, hence explaining its capacity to mediate immune-dependent therapeutic effects. Citation Format: HENG ZHOU, Allan Sauvat, Sylvère Durand, Sabrina Forveille, Takahiro Yamazaki, Sylvie Souquere, Valentina Sica, Øystein Rekdal, Oliver Kepp, Guido Kroemer. Mode of action of LTX315-induced cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4309. doi:10.1158/1538-7445.AM2017-4309 |
| تدمد: | 1538-7445 0008-5472 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::cc561b8300c2ff7885ee1b80af4f3713Test https://doi.org/10.1158/1538-7445.am2017-4309Test |
| رقم الانضمام: | edsair.doi...........cc561b8300c2ff7885ee1b80af4f3713 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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