Journal
ONCOLOGY LETTERS
Volume 10, Issue 4, Pages 2192-2196Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ol.2015.3545
Keywords
bortezomib; hypoxia-inducible factor; HIF-1; HIF-2; transcriptional activity
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Funding
- Malaysian government [04-01-11-1159RU, 09-05-IFN-BPH-009, 02-01-04-SF1269, 05-02-12-2010RU]
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Bortezomib is the first proteasomal inhibitor (PI) to be used therapeutically for treating relapse cases of multiple myeloma and mantle cell lymphoma. A proposed mechanism for its action is that it prevents the proteasomal degradation of proapoptotic proteins, leading to enhanced apoptosis. Although the a subunit of hypoxia-inducible factor (HIF)-1 is not degraded with bortezomib treatment, the heterodimeric HIF-1 fails to transactivate target genes. HIP-1 and HIF-2 are related hypoxia-inducible transcription factors that are important for the survival of hypoxic tumor cells. The majority of reports have focused on the effects of bortezomib on the transcriptional activities of HIP-1, but not HIF-2. The present study investigated the effects of bortezomib on HIP-2 activity in cancer cells with different levels of HIP-1 alpha and HIP-2 alpha subunits. HIF-alpha subunit levels were detected using specific antibodies, while HIF transcriptional activities were evaluated using immunodetection, reverse transcription-polymerase chain reaction and luciferase reporter assay. Bortezomib treatment was found to suppress the transcription and expression of CA9, a HIP-1-specific target gene; however, it had minimal effects on EPO and GLUT-I, which are target genes of both HIP-1 and HIP-2. These data suggest that bortezomib attenuates the transcriptional activity only of HIF-1, and not HIP-2. This novel finding on the lack of an inhibitory effect of bortezomib on HIP-2 transcriptional activity has implications for the improvement of design and treatment modalities of bortezomib and other PI drugs.
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