TY - JOUR
T1 - The oncolytic compound LTX-401 targets the Golgi apparatus
AU - Zhou, Heng
AU - Sauvat, Allan
AU - Gomes-Da-Silva, Lígia C.
AU - Durand, Sylvère
AU - Forveille, Sabrina
AU - Iribarren, Kristina
AU - Yamazaki, Takahiro
AU - Souquere, Sylvie
AU - Bezu, Lucillia
AU - Müller, Kevin
AU - Leduc, Marion
AU - Liu, Peng
AU - Zhao, Liwei
AU - Marabelle, Aurélien
AU - Zitvogel, Laurence
AU - Rekdal, Øystein
AU - Kepp, Oliver
AU - Kroemer, Guido
N1 - Publisher Copyright:
© 2016 Macmillan Publishers Limited, part of Springer Nature.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - LTX-401 is an oncolytic amino acid derivative with potential immunogenic properties. Here, we demonstrate that LTX-401 selectively destroys the structure of the Golgi apparatus, as determined by means of ultrastructural analyses and fluorescence microscopic observation of cells expressing Golgi-targeted GFP reporters. Subcellular fractionation followed by mass spectrometric detection revealed that LTX-401 selectively enriched in the Golgi rather than in mitochondria or in the cytosol. The Golgi-dissociating agent Brefeldin A (BFA) reduced cell killing by LTX-401 as it partially inhibited LTX-401-induced mitochondrial release of cytochrome c and the activation of BAX. The cytotoxic effect of LTX-401 was attenuated by the double knockout of BAX and BAK, as well as the mitophagy-enforced depletion of mitochondria, yet was refractory to caspase inhibition. LTX-401 induced all major hallmarks of immunogenic cell death detectable with biosensor cell lines including calreticulin exposure, ATP release, HMGB1 exodus and a type-1 interferon response. Moreover, LTX-401-treated tumors manifested a strong lymphoid infiltration. Altogether these results support the contention that LTX-401 can stimulate immunogenic cell death through a pathway in which Golgi-localized LTX-401 operates upstream of mitochondrial membrane permeabilization.
AB - LTX-401 is an oncolytic amino acid derivative with potential immunogenic properties. Here, we demonstrate that LTX-401 selectively destroys the structure of the Golgi apparatus, as determined by means of ultrastructural analyses and fluorescence microscopic observation of cells expressing Golgi-targeted GFP reporters. Subcellular fractionation followed by mass spectrometric detection revealed that LTX-401 selectively enriched in the Golgi rather than in mitochondria or in the cytosol. The Golgi-dissociating agent Brefeldin A (BFA) reduced cell killing by LTX-401 as it partially inhibited LTX-401-induced mitochondrial release of cytochrome c and the activation of BAX. The cytotoxic effect of LTX-401 was attenuated by the double knockout of BAX and BAK, as well as the mitophagy-enforced depletion of mitochondria, yet was refractory to caspase inhibition. LTX-401 induced all major hallmarks of immunogenic cell death detectable with biosensor cell lines including calreticulin exposure, ATP release, HMGB1 exodus and a type-1 interferon response. Moreover, LTX-401-treated tumors manifested a strong lymphoid infiltration. Altogether these results support the contention that LTX-401 can stimulate immunogenic cell death through a pathway in which Golgi-localized LTX-401 operates upstream of mitochondrial membrane permeabilization.
UR - http://www.scopus.com/inward/record.url?scp=84984889480&partnerID=8YFLogxK
U2 - 10.1038/cdd.2016.86
DO - 10.1038/cdd.2016.86
M3 - Article
C2 - 27588704
AN - SCOPUS:84984889480
SN - 1350-9047
VL - 23
SP - 2031
EP - 2041
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 12
ER -