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

Abstract

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 induce 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 by 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 consequence of ER stress induction. In HCT116 cells, ER stress stimulated autophagy, assessed by the accumulation of the lipidated form of LC3. The inhibitor of ER stress mannose attenuated autophagy and reversed 2-DG-mediated suppression of cisplatin-induced apoptosis. When autophagy in HCT116 cells was suppressed by bafilomycin, cisplatin-induced apoptosis was decreased. At the same time, stimulation of autophagy in SK-N-BE(2) cells suppressed cell death. Thus, successful treatment of tumors with conventionally used anticancer drugs should be combined with targeting metabolic pathways involved in the regulation of apoptosis, autophagy, and cellular bioenergetics.

• Authors: Polina Maximchik, Alibek Abdrakhmanov, Evgeniya Inozemtseva, Pyotr A Tyurin-Kuzmin, Boris Zhivotovsky, Vladimir Gogvadze
• Journal: The FEBS journal (FEBS J) Vol. 285 Issue 24 Pg. 4590-4601 (12 2018) ISSN: 1742-4658 [Electronic] England
• PMID: 30375744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Federation of European Biochemical Societies.

Chemical References

• Antimetabolites
• Antineoplastic Agents
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Deoxyglucose
• Cisplatin

Topics

• Antimetabolites (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Autophagy
• Cell Lineage
• Cell Proliferation
• Cisplatin (pharmacology)
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• Deoxyglucose (pharmacology)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress
• Humans
• Mitochondria (drug effects, metabolism, pathology)
• Neuroblastoma (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured