HSP90 inhibitor 17-AAG selectively eradicates lymphoma stem cells.

Abstract

Cancer stem cells (CSC; also called tumor-initiating cells) comprise tumor cell subpopulations that preserve the properties of quiescence, self-renewal, and differentiation of normal stem cells. In addition, CSCs are therapeutically important because of their key contributions toward drug resistance. The hypoxia-inducible transcription factor HIF1α is critical for CSC maintenance in mouse lymphoma. In this study, we showed that low concentrations of the HSP90 inhibitor 17-AAG eliminate lymphoma CSCs in vitro and in vivo by disrupting the transcriptional function of HIF1α, a client protein of HSP90. 17-AAG preferentially induced apoptosis and eliminated the colony formation capacity of mouse lymphoma CSCs and human acute myeloid leukemia (AML) CSCs. However, low concentrations of 17-AAG failed to eliminate highly proliferative lymphoma and AML cells (non-CSCs), in which the AKT-GSK3 signaling pathway is constitutively active. The heat shock transcription factor HSF1 is highly expressed in non-CSCs, but it was weakly expressed in lymphoma CSCs. However, siRNA-mediated attenuation of HSF1 abrogated the colony formation ability of both lymphoma and AML CSCs. This study supports the use of 17-AAG as a CSC targeting agent and, in addition, shows that HSF1 is an important target for elimination of both CSCs and non-CSCs in cancer.

• Authors: Bryan Newman, Yan Liu, Hsiu-Fang Lee, Duxin Sun, Yin Wang
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 17 Pg. 4551-61 (Sep 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22751135 (Publication Type: Journal Article)
• Copyright: ©2012 AACR.

Chemical References

• Benzoquinones
• DNA-Binding Proteins
• HSP90 Heat-Shock Proteins
• Heat Shock Transcription Factors
• Hsf1 protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lactams, Macrocyclic
• Transcription Factors
• tanespimycin

Topics

• Animals
• Benzoquinones (pharmacology)
• Cell Line, Tumor
• DNA-Binding Proteins (genetics, metabolism)
• Gene Silencing
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism)
• Heat Shock Transcription Factors
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Lactams, Macrocyclic (pharmacology)
• Leukemia, Myeloid, Acute (metabolism)
• Lymphoma (genetics, metabolism)
• Mice
• Mice, SCID
• Neoplastic Stem Cells (drug effects, metabolism)
• Signal Transduction (drug effects)
• Transcription Factors (genetics, metabolism)