Aberrant DR5 transport through disruption of lysosomal function suggests a novel mechanism for receptor activation

0471956 - BFÚ 2017 RIV US eng J - Journal Article
Akpinar, B. - Šafaříková, Barbora - Lauková, Jarmila - Debnath, S. - Vaculová, Alena - Zhivotovsky, B. - Olsson, M.
Aberrant DR5 transport through disruption of lysosomal function suggests a novel mechanism for receptor activation.
OncoTarget. Roč. 7, č. 36 (2016), s. 58286-58301. ISSN 1949-2553
R&D Projects: GA ČR GA15-06650S
Institutional support: RVO:68081707
Keywords : death ligand trail * dependent apoptosis * cancer-cells * autophagy
Subject RIV: BO - Biophysics
Impact factor: 5.168, year: 2016

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.
Permanent Link: http://hdl.handle.net/11104/0269317