Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 119, Issue 6, Pages 4907-4917Publisher
WILEY
DOI: 10.1002/jcb.26718
Keywords
2-DG; aerobic glycolysis; c-Myc; ER stress; LDH A; LDH B; miR-23a; thapsigargin
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Funding
- Department of Biotechnology, Ministry of Science and Technology, Government of India [6242-P48/RGCB/PMD/DBT/VBSK/2015]
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Cancer cells exhibit increased dependency on aerobic glycolysis, a phenomenon referred as the Warburg effect and therefore, blocking glycolysis by using non-metabolizable analogues of glucose, like 2-Deoxy glucose (2-DG), has been proposed to be of huge therapeutic importance. One of the major drawbacks of using 2-DG as a chemotherapeutic agent is that it can induce ER stress. ER stress is a hall mark in many solid tumors and the unfolded protein response (UPR) associated with it initiates many survival mechanisms in cancer cells. In the present study, we report a novel survival mechanism associated with ER stress, by which the cancer cells become more adapted to aerobic glycolysis. When ER stress was induced in Hela cells by treating them with 2-DG or Thapsigargin (TG) the expression and activity of LDH was significantly up regulated, conferring the cells a greater glycolytic potential. A simultaneous decrease was observed in the expression of miR-23a, which was predicted in silico to have target site on the 3UTR of LDH A and B mRNAs. miRNA over expression studies and mRNA degradation assays suggest that miR-23a could target LDH A and LDH B mRNAs. Further on the basis of our results and previous scientific reports, we propose that c-Myc, which is over expressed during ER stress, repress the expression of miR-23a, which in turn regulates the expression of its target genes viz., LDH A and LDH B, thereby making the cells more competent to survive in tumor microenvironment, which requires efficient use of aerobic glycolysis.
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