2 ‐Deoxy‐D‐glucose has distinct and cell line‐specific effects on the survival of different cancer cells upon antitumor drug treatment

Suppression of glycolysis by 2 ‐deoxy‐D‐glucose (2‐DG) stimulates apoptosis in SK‐N‐BE(2), but attenuates in HCT116 cells. In both cell lines 2‐DG stimulates stress of endoplasmic reticulum (ER), which ends up in apoptosis in SK‐N‐BE(2) but in autophagy in HCT116 cells. Prevention of ER stress by mannose attenua tes apoptosis in SK‐N‐BE(2) cells, and reverses suppression of apoptosis in HCT116 cells. The dependence of tumors on glycolysis for ATP generation offers a rationale for therapeutic strategies aimed at selective inhibition of the glycolytic pathway. Analysis of tumor cell responses to anticancer drugs revealed that inhibition of glycolysis by 2 ‐deoxy‐D‐glucose (2‐DG) generally augmented the apoptotic response; however, in HCT116 human colon carcinoma cells, apoptosis was suppressed. A comparison of neuroblastoma SK‐N‐BE(2) and HCT116 cells revealed, that in contrast to HCT116, in SK‐N‐BE(2) cells 2‐DG alone was able to i nduce cell death. In SK‐N‐BE(2) cells the decrease in ATP levels upon treatment with 2‐DG was more prominent because in HCT116 cells mitochondria compensated for the loss of ATP caused by glycolysis suppression. In both cells lines 2‐DG triggered endoplasmic reticulum (ER) stress, assessed b y the accumulation of the marker protein GRP78/BiP. Suppression of ER stress by mannose attenuated the 2‐DG‐induced apoptotic response in SK‐N‐BE(2) cells, implying that apoptosis in these cells is a conseq...
Source: FEBS Journal - Category: Research Authors: Tags: Original Article Source Type: research