HIF-1α inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression.

Abstract

BACKGROUND:

Hypoxia induces activation of the HIF-1 pathway and is an essential characteristic of malignant gliomas. Hypoxia has been linked to tumor progression, therapy resistance and poor prognosis. However, little is known about the impact of HIF-1α inhibition on radioresistance of malignant glioma.

METHODS:

In this study, we investigated the effects of the inhibition of HIF-1α on cell survival and radiosensitivity in U251MG and U343MG glioma cells, using two different strategies. HIF-1α inhibition was achieved by siRNA targeting of HIF-1α or via chetomin, a disruptor of interactions between HIF-1α and p300. The inhibition of the HIF-1 pathway was monitored by quantitative real-time PCR and Western blot analyses of the expression levels of HIF-1α and CA9. CA9 expression was investigated as a potential indicator of the efficacy of HIF-1 inhibition and the resulting radiosensitivity of malignant glioma cell lines was determined by clonogenic assay after irradiation under normoxic (2-10 Gy) or hypoxic (2-15 Gy) conditions.

RESULTS:

Although siRNA and chetomin show distinct modes of action, both attenuated the hypoxia-induced radioresistance of malignant glioma cell lines U251MG (DMF10: 1.35 and 1.18) and U343MG (DMF10: 1.78 and 1.48). However, siRNA and chetomin showed diverse effects on radiosensitivity under normoxic conditions in U251MG (DMF10: 0.86 and 1.35) and U343MG (DMF10: 1.33 and 1.02) cells.

CONCLUSIONS:

Results from this in vitro study suggest that inhibition of HIF-1α is a promising strategy to sensitize human malignant gliomas to radiotherapy and that CA9 could serve as an indicator of effective HIF-1-related radiosensitization.

• Authors: Jacqueline Kessler, Antje Hahnel, Henri Wichmann, Swetlana Rot, Matthias Kappler, Matthias Bache, Dirk Vordermark
• Journal: BMC cancer (BMC Cancer) Vol. 10 Pg. 605 (Nov 04 2010) ISSN: 1471-2407 [Electronic] England
• PMID: 21050481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Antineoplastic Agents
• Disulfides
• Hypoxia-Inducible Factor 1, alpha Subunit
• Indole Alkaloids
• RNA, Small Interfering
• chetomin
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases

Topics

• Antigens, Neoplasm (biosynthesis)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Carbonic Anhydrase IX
• Carbonic Anhydrases (biosynthesis)
• Cell Line, Tumor
• Cell Survival
• Disease Progression
• Disulfides (pharmacology)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Glioma (metabolism)
• Humans
• Hypoxia
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Indole Alkaloids (pharmacology)
• RNA, Small Interfering (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction