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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

BO - Biofyzika

OECD FORD obor

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Projekt

<a href="/cs/project/GA15-06650S" target="_blank" >GA15-06650S: Nové molekulární mechanismy smrti nádorových buněk indukované chemoterapeutickými látkami a cytokiny</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

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

Název periodika

OncoTarget

ISSN

1949-2553

e-ISSN

—

Svazek periodika

7

Číslo periodika v rámci svazku

36

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

16

Strana od-do

58286-58301

Kód UT WoS článku

000387153200067

EID výsledku v databázi Scopus

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