Journal
CANCER RESEARCH
Volume 72, Issue 1, Pages 304-314Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-11-1674
Keywords
-
Categories
Funding
- NIH [CA016672, T32 CA009599]
- Texas Emerging Technology Fund [300-9-1958]
- Center of Nuclear Receptors and Cell Signaling of University of Houston
- American Cancer Society
- Department of Defense
- William C. Liedtke, Jr. Chair in Cancer Research
Ask authors/readers for more resources
Altered metabolism in cancer cells is suspected to contribute to chemoresistance, but the precise mechanisms are unclear. Here, we show that intracellular ATP levels are a core determinant in the development of acquired cross-drug resistance of human colon cancer cells that harbor different genetic backgrounds. Drug-resistant cells were characterized by defective mitochondrial ATP production, elevated aerobic glycolysis, higher absolute levels of intracellular ATP, and enhanced HIF-1 alpha-mediated signaling. Interestingly, direct delivery of ATP into cross-chemoresistant cells destabilized HIF-1 alpha and inhibited glycolysis. Thus, drug-resistant cells exhibit a greater ATP debt defined as the extra amount of ATP needed to maintain homeostasis of survival pathways under genotoxic stress. Direct delivery of ATP was sufficient to render drug-sensitive cells drug resistant. Conversely, depleting ATP by cell treatment with an inhibitor of glycolysis, 3-bromopyruvate, was sufficient to sensitize cells cross-resistant to multiple chemotherapeutic drugs. In revealing that intracellular ATP levels are a core determinant of chemoresistance in colon cancer cells, our findings may offer a foundation for new improvements to colon cancer treatment. Cancer Res; 72(1); 304-14. (C) 2011 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available