The level of BCR-ABL expression increases as tumors progress from the chronic phase (Gorre et al., 2001
). Increased BCR-ABL has also been observed when BCR-ABL transformed cells are selected for imatinib resistance in vitro
(Mahon et al., 2000
) (). Surprisingly, here we show imatinib-resistant cells displayed an increase in glycolysis but a reduced rate of proliferation. The effect is reminiscent of the effects of HIF-1α induction in cells exhibiting aerobic glycolysis (Lum et al., 2007
). We demonstrate that HIF-1α was induced in response to high levels of BCR-ABL expression and was required to maintain the viability of such cells. The observed BCR-ABL induction of HIF-1α appears to lead to a relatively sustained conversion to aerobic glycolysis just as hypoxic induction of HIF-1α leads to sustained anaerobic glycolysis.
Cells with high levels of BCR-ABL expression are at a growth disadvantage in comparison to cells with low levels of BCR-ABL when BCR-ABL-induced glucose metabolism exceeds the capacity of a cell to assimilate or store glucose-derived carbon. BCR-ABL induces increased expression of HIF-1α and glucose uptake. In part, BCR-ABL has been reported to increase HIF-1α through PI3K activation (Mayerhofer et al., 2002
). The BCR-ABL induction of HIF-1α redirects glucose metabolism away from mitochondria (Gottschalk et al., 2004
). While the induction of HIF-1α in response to excess glucose catabolism (Zhang et al., 2008
) or hypoxia (Giuntoli et al., 2006
) is cytoprotective, activation of HIF-1α reduces the synthetic capacity of the mitochondria and diverts glucose metabolism away from the oxidative arm of the PPP (Lum et al., 2007
). The resulting decrease in the production of fatty acids, TCA-cycle-derived non-essential amino acids, and ribose correlated with a reduced ability to proliferate. Thus, even in transformed cells, there appears to be a level of glucose metabolism that can paradoxically suppress in cis
the proliferation of a cell.
Most cancer cells depend on de novo
nucleotide biosynthesis for growth and survival (Zaharevitz et al., 1992
). This has been exploited in cancer therapy through the use of inhibitors of dihydrofolate reductase, thymidylate synthase, glutamine phosphoribosylpyrophosphate amidotransferase and adenosine deaminase. Ribose can be produced both in the oxidative and non-oxidative arms of the PPP. This has been interpreted to mean that an effective inhibitor of ribose synthesis would have to block both arms. Such drugs might thus have heightened toxicities for normal cells. Our data suggest that in cells depending on HIF-1α for continuous survival, effective ribose synthesis can only be maintained from the non-oxidative arm of the PPP. This suggests that inhibitors of the non-oxidative PPP may have selective effects in tumors exhibiting constitutive HIF-1α activation. Such a targeted therapeutic use may limit the toxicity for non-transformed cells that retain an intact oxidative arm of the PPP. Consistent with this, oxythiamine, an inhibitor of thiamine dependent enzymes, was found to synergize with imatinib in suppressing the growth and proliferation of BCR-ABL transformed cells in vitro
. How long such an effect can be sustained in chronically treated cells will require additional study.
In conclusion, our study provides insight into relative imatinib resistance associated with the increased BCR-ABL expression observed in leukemic cells of patients with accelerated CML. Collectively, the above observations support the hypothesis that the induction of HIF-1α may contribute to the imatinib resistance exhibited by such cells. The ongoing development of HIF-1α inhibitors may soon allow this hypothesis to be tested. The potential ability of HIF-1α induction to reduce the oncogene addiction of BCR-ABL transformed cells may be relevant to other oncogenes that activate the glucose metabolism of transformed cells, and this will need to be explored in future studies.