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

Abstract

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.

The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5

“…7 ). In agreement with our findings, another recent study also reported that CQ induced cytoplasmic localization of DR5 and did not modulate TRAIL-induced apoptosis in human colon cancer HCT116 cells 38 . Moreover lysosome inhibition induced an additional isoform of DR5 protein smaller than 40 kD (Fig.…”

Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5

“…Furthermore, co-localization studies showed higher levels of DR5 and LAMP-1 double-positive vesicles in HTNV-infected compared to uninfected cells ( Figures 7B, 7C, and S6). Chloroquine (CQ) has been shown to induce DR5 accumulation in lysosomes (Akpinar et al, 2016). Mirroring observations in HTNV-infected cells, perinuclear accumulation of DR5 and increased levels of DR5 and LAMP-1 double-positive vesicles were observed in CQ-treated uninfected cells ( Figures 7B and 7C).…”

TRAIL DR5-CTSB crosstalk participates in breast cancer autophagy initiated by SAHA

“… 5–8 Studies have also shown that TRAIL DR5 can trigger autophagy-related pathways and cause cell death. 9–12 …”