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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F16%3A00471956" target="_blank" >RIV/68081707:_____/16:00471956 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.18632/oncotarget.11073" target="_blank" >http://dx.doi.org/10.18632/oncotarget.11073</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.18632/oncotarget.11073" target="_blank" >10.18632/oncotarget.11073</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

BO - Biophysics

OECD FORD branch

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Project

<a href="/en/project/GA15-06650S" target="_blank" >GA15-06650S: Novel molecular mechanisms involved in chemotherapeutic drug- and cytokine-induced cancer cell death</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

OncoTarget

ISSN

1949-2553

e-ISSN

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Volume of the periodical

7

Issue of the periodical within the volume

36

Country of publishing house

US - UNITED STATES

Number of pages

16

Pages from-to

58286-58301

UT code for WoS article

000387153200067

EID of the result in the Scopus database

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