A unique glucose-dependent apoptotic pathway induced by c-Myc

A unique glucose-dependent apoptotic pathway induced by c-Myc

^*Department of Medicine, ^†Program in Human Genetics and Molecular Biology, Departments of ^‡Molecular Biology and Genetics and ^§Pathology, and ^¶The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205

Edited by Stanley J. Korsmeyer, Washington University School of Medicine, St. Louis, MO, and approved December 12, 1997 (received for review August 7, 1997)

Abstract

The lactate dehydrogenase A (LDH-A) gene, whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, has been identified as a c-Myc-responsive gene. It was of interest, therefore, to compare the effect of glucose deprivation in c-Myc-transformed and nontransformed cells. We observed that glucose deprivation or treatment with the glucose antimetabolite 2-deoxyglucose caused nontransformed cells to arrest in the G₀/G₁ phase of the cell cycle. In contrast, c-Myc-transformed fibroblasts, lymphoblastoid, or lung carcinoma cells underwent extensive apoptosis. Ectopic expression of LDH-A alone in Rat1a fibroblasts was sufficient to induce apoptosis with glucose deprivation but not with serum withdrawal, suggesting that LDH-A mediates the unique apoptotic effect of c-Myc when glycolysis is blocked. The apoptosis caused by glucose deprivation was blocked by Bcl-2 expression but appeared to be independent of wild-type p53 activity. These studies provide insights on the coupling of glucose metabolism and the cell cycle in c-Myc-transformed cells and may in the future be exploited for cancer therapeutics.

Footnotes

↵ ‖ To whom reprint requests should be addressed at: Ross Research Building, Room 1025, Johns Hopkins Medical School, 720 Rutland Avenue, Baltimore, MD 21205. e-mail: cvdang{at}welchlink.welch.jhu.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: FBS, fetal bovine serum; BrdUrd, bromodeoxyuridine; TdT, terminal deoxynucleotidyltransferase; 2-DG, 2-deoxyglucose.