TY - JOUR
T1 - Inhibition of glycolysis in cancer cells
T2 - A novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia
AU - Xu, Rui Hua
AU - Pelicano, Helene
AU - Zhou, Yan
AU - Carew, Jennifer S.
AU - Feng, Li
AU - Bhalla, Kapil N.
AU - Keating, Michael J.
AU - Huang, Peng
PY - 2005/1/15
Y1 - 2005/1/15
N2 - Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser112, relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warhurg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.
AB - Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser112, relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warhurg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.
UR - http://www.scopus.com/inward/record.url?scp=12544256565&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=12544256565&partnerID=8YFLogxK
M3 - Article
C2 - 15695406
AN - SCOPUS:12544256565
SN - 0008-5472
VL - 65
SP - 613
EP - 621
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -