Abstract
Down-regulation by small interfering RNA or absence of hypoxia-inducible factor (HIF-1α) has been shown to lead to increased sensitivity to glycolytic inhibitors in hypoxic tumor cells. In surveying a number of tumor types for differences in intrinsic levels of HIF under hypoxia, we find that the reduction of the upstream pathways of HIF, AKT, and mammalian target of rapamycin (mTOR) correlates with increased toxic effects of 2-deoxy-D-glucose (2-DG) in lung cancer cell lines when treated under hypoxia. Because HIF-1α translation is regulated by mTOR, we examined the effects of blocking mTOR under hypoxia with an analogue of rapamycin (CCI-779) in those cell lines that showed increased mTOR and AKT activity and found that HIF-1α down-regulation coincided with increased 2-DG killing. CCI-779, however, was ineffective in increasing 2-DG toxicity in cell lines that did not express HIF. These results support the hypothesis that although mTOR inhibition leads to the blockage of numerous downstream targets, CCI-779 increases the toxicity of 2-DG in hypoxic cells through down-regulation of HIF-1α. Overall, our findings show that CCI-779 hypersensitizes hypoxic tumor cells to 2-DG and suggests that the intrinsic expression of AKT, mTOR, and HIF in lung cancer, as well as other tumor types, may be important in dictating the decision on how best to use 2-DG alone or in combination with CCI-799 to kill hypoxic tumor cells clinically.
| Original language | English |
|---|---|
| Pages (from-to) | 1506-1513 |
| Number of pages | 8 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 7 |
| Issue number | 6 |
| DOIs | |
| State | Published - Oct 15 2008 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
- Drug Discovery
- Pharmacology
Cite this
Intrinsically lower AKT, mammalian target of rapamycin, and hypoxia-inducible factor activity correlates with increased sensitivity to 2-deoxy-D-glucose under hypoxia in lung cancer cell lines. / Wangpaichitr, Medhi; Savaraj, Niramol; Maher, Johnathan; Kurtoglu, Metin; Lampidis, Theodore.
In: Molecular Cancer Therapeutics, Vol. 7, No. 6, 15.10.2008, p. 1506-1513.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Intrinsically lower AKT, mammalian target of rapamycin, and hypoxia-inducible factor activity correlates with increased sensitivity to 2-deoxy-D-glucose under hypoxia in lung cancer cell lines
AU - Wangpaichitr, Medhi
AU - Savaraj, Niramol
AU - Maher, Johnathan
AU - Kurtoglu, Metin
AU - Lampidis, Theodore
PY - 2008/10/15
Y1 - 2008/10/15
N2 - Down-regulation by small interfering RNA or absence of hypoxia-inducible factor (HIF-1α) has been shown to lead to increased sensitivity to glycolytic inhibitors in hypoxic tumor cells. In surveying a number of tumor types for differences in intrinsic levels of HIF under hypoxia, we find that the reduction of the upstream pathways of HIF, AKT, and mammalian target of rapamycin (mTOR) correlates with increased toxic effects of 2-deoxy-D-glucose (2-DG) in lung cancer cell lines when treated under hypoxia. Because HIF-1α translation is regulated by mTOR, we examined the effects of blocking mTOR under hypoxia with an analogue of rapamycin (CCI-779) in those cell lines that showed increased mTOR and AKT activity and found that HIF-1α down-regulation coincided with increased 2-DG killing. CCI-779, however, was ineffective in increasing 2-DG toxicity in cell lines that did not express HIF. These results support the hypothesis that although mTOR inhibition leads to the blockage of numerous downstream targets, CCI-779 increases the toxicity of 2-DG in hypoxic cells through down-regulation of HIF-1α. Overall, our findings show that CCI-779 hypersensitizes hypoxic tumor cells to 2-DG and suggests that the intrinsic expression of AKT, mTOR, and HIF in lung cancer, as well as other tumor types, may be important in dictating the decision on how best to use 2-DG alone or in combination with CCI-799 to kill hypoxic tumor cells clinically.
AB - Down-regulation by small interfering RNA or absence of hypoxia-inducible factor (HIF-1α) has been shown to lead to increased sensitivity to glycolytic inhibitors in hypoxic tumor cells. In surveying a number of tumor types for differences in intrinsic levels of HIF under hypoxia, we find that the reduction of the upstream pathways of HIF, AKT, and mammalian target of rapamycin (mTOR) correlates with increased toxic effects of 2-deoxy-D-glucose (2-DG) in lung cancer cell lines when treated under hypoxia. Because HIF-1α translation is regulated by mTOR, we examined the effects of blocking mTOR under hypoxia with an analogue of rapamycin (CCI-779) in those cell lines that showed increased mTOR and AKT activity and found that HIF-1α down-regulation coincided with increased 2-DG killing. CCI-779, however, was ineffective in increasing 2-DG toxicity in cell lines that did not express HIF. These results support the hypothesis that although mTOR inhibition leads to the blockage of numerous downstream targets, CCI-779 increases the toxicity of 2-DG in hypoxic cells through down-regulation of HIF-1α. Overall, our findings show that CCI-779 hypersensitizes hypoxic tumor cells to 2-DG and suggests that the intrinsic expression of AKT, mTOR, and HIF in lung cancer, as well as other tumor types, may be important in dictating the decision on how best to use 2-DG alone or in combination with CCI-799 to kill hypoxic tumor cells clinically.
UR - http://www.scopus.com/inward/record.url?scp=49849099471&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=49849099471&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-07-2334
DO - 10.1158/1535-7163.MCT-07-2334
M3 - Article
C2 - 18566221
AN - SCOPUS:49849099471
VL - 7
SP - 1506
EP - 1513
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 6
ER -