Number of the records: 1
Aberrant DR5 transport through disruption of lysosomal function suggests a novel mechanism for receptor activation
- 1.
SYSNO ASEP 0471956 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Aberrant DR5 transport through disruption of lysosomal function suggests a novel mechanism for receptor activation Author(s) Akpinar, B. (SE)
Šafaříková, Barbora (BFU-R)
Lauková, Jarmila (BFU-R)
Debnath, S. (SE)
Vaculová, Alena (BFU-R) RID, ORCID
Zhivotovsky, B. (SE)
Olsson, M. (SE)Number of authors 7 Source Title OncoTarget. - : Impact Journals LLC - ISSN 1949-2553
Roč. 7, č. 36 (2016), s. 58286-58301Number of pages 16 s. Publication form Print - P Language eng - English Country US - United States Keywords death ligand trail ; dependent apoptosis ; cancer-cells ; autophagy Subject RIV BO - Biophysics R&D Projects GA15-06650S GA ČR - Czech Science Foundation (CSF) Institutional support BFU-R - RVO:68081707 UT WOS 000387153200067 DOI 10.18632/oncotarget.11073 Annotation To examine reciprocal or unilateral implications between two cell destruction processes, autophagy and apoptosis, in 5-Fluorouracil (5-FU)-treated tumor cells, a combination of chemical inhibitors, RNAi and genetic approaches were used. In contrast to cancer cells harboring obstructed apoptosis, either at the DISC or the mitochondrial level, p53-deficiency generated signs of autophagy deregulation upon chemotherapy. On the other, hand disruption of lysosomal function by chloroquine, caused a profound decrease in apoptotic markers appearing in response to 5-FU. DR5, which is essential for 5-FU-induced apoptosis, accumulated in lysosomes and autophagosomes upon chloroquine treatment. Since neither 3-MA, RNAi of critical autophagy regulators or inhibition of cathepsins reversed apoptosis in a similar manner, it is likely that not autophagy per se but rather correct receptor transport is an important factor for 5-FU cytotoxicity. We found that apoptosis generated by TRAIL, the cognate ligand for DR5, remained unchanged upon chloroquine lysosomal interference, indicating that 5-FU activates the receptor by a discrete mechanism. In support, depletion of membrane cholesterol or hampering cholesterol transport drastically reduced 5-FU cytotoxicity. We conclude that targeting of lysosomes by chloroquine deregulates DR5 trafficking and abrogates 5-FU-but not TRAIL-stimulated cell elimination, hence suggesting a novel mechanism for receptor activation. Workplace Institute of Biophysics Contact Jana Poláková, polakova@ibp.cz, Tel.: 541 517 244 Year of Publishing 2017
Number of the records: 1