Abstract
Carcinogenesis and cancer progression, driven by mutations in oncogenes and tumor-suppressor genes, result in biological differences between normal and cancer cells in various cellular processes. Specific genes and signaling molecules involved in such cellular processes may be potential therapeutic targets of agents that specifically interact with the key factors in cancer cells. Increased glucose uptake is fundamental to many solid tumors and well associated with increases in glycolysis and the overexpression of glucose transporters (GLUTs) such as GLUT1 and GLUT3 at the plasma membrane. Here, we used cell-based screening to identify glycogen synthase kinase-3β (GSK-3β) inhibitors that selectively target GLUT3-expressing tumorigenic HeLa cell hybrids as compared with non-tumorigenic hybrids that express GLUT1 alone. The GSK-3 inhibitors as well as GSK-3β RNAi suppressed GLUT3 expression at the level of transcription, leading to apoptosis. This suppression was associated with NF-κB in a p53-independent manner. Furthermore, GSK-3 inhibitors exhibited a synergistic effect with anticancer agents such as adriamycin and camptothecin in GULT3-overexpressing colon cancer cells, but little effect in non-producing A431 cells. These results suggest a potential use of GSK-3 inhibitors to selectively kill cancer cells that overexpress GLUT3.
Highlights
One of the most important considerations in cancer chemotherapy is selective killing of cancer cells without significant toxicity to normal cells
The expression of GLUT1 was Chemical screening for inhibitors that predominantly inhibit the growth of cancer cells
We have reported that a tumorigenic HeLa cell hybrid CGL4 expressed GLUT3, which was undetectable in non-tumorigenic CGL1 cells.[34]
Summary
One of the most important considerations in cancer chemotherapy is selective killing of cancer cells without significant toxicity to normal cells. Understanding the physiological differences between normal and cancer cells is essential for the design and development of anticancer drugs with selective anticancer activities. Cancer cells are well known to have accelerated metabolism, higher glucose requirements and increased glucose uptake.[1,2,3,4,5] these characteristics are often associated with increased metastasis and poor survival in cancer patients[6,7,8,9] and have been clinically applied to tumor imaging with positron emission tomography.[10,11]. GLUT1, one of the most intensively studied of all membrane transport proteins, is widely expressed in proliferating cells.[13,14] GLUT3 is the major neuronal glucose transporter predominantly expressed in neuronal cells.[13,15] In addition, strong expression of both the isoforms is observed in many tumors, such as gliomas, non-small cell lung carcinomas, gastroenterological tumors and ovarian carcinomas.[16,17,18,19] Upregulated expression of the GLUT family is often closely associated with malignancy,[12,20] the specific genes and signaling pathways regulating the expression remain undefined
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