| First Author | Newman B | Year | 2012 |
| Journal | Cancer Res | Volume | 72 |
| Issue | 17 | Pages | 4551-61 |
| PubMed ID | 22751135 | Mgi Jnum | J:191025 |
| Mgi Id | MGI:5451165 | Doi | 10.1158/0008-5472.CAN-11-3600 |
| Citation | Newman B, et al. (2012) HSP90 inhibitor 17-AAG selectively eradicates lymphoma stem cells. Cancer Res 72(17):4551-61 |
| abstractText | 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 HIF1alpha 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 HIF1alpha, 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. |
