HSP90 inhibitor 17-AAG selectively eradicates lymphoma stem cells.
HSP90 inhibitor 17-AAG selectively eradicates lymphoma stem cells.
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DOI：
10.1158/0008-5472.can-11-3600
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发表时间：
2012-09-01
期刊：
影响因子：
11.2
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Newman B;Liu Y;Lee HF;Sun D;Wang Y
Cancer stem cells (CSCs, also called tumor initiating cells) comprise tumor cell subpopulations that preserve the properties of quiescence, self-renewal and differentiation of normal stem cells. CSCs are also therapeutically important because of their key contributions to drug resistance. The hypoxia inducible transcription factor HIF1α is critical for CSC maintenance in mouse lymphoma. Here we show 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 it also shows that HSF1 is an important target for elimination of both CSCs and non-CSCs in cancer.
