HSP90 Inhibitor 17-AAG Selectively Eradicates Lymphoma Stem Cells

Abstract

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.

Transcriptomic profiling of curcumin-treated human breast stem cells identifies a role for stearoyl-coa desaturase in breast cancer prevention

“…Interestingly, cancer stem cells have been shown to be more sensitive to inhibition of heat shock proteins than bulk cancer cells. Targeting HSP90 with low concentrations of the inhibitory drug 17-AAG significantly inhibited lymphoma stem cells [33]. Treatment of breast cancer cells with both HSP90 and HSP27 inhibitors lead to a significant reduction in the stem- like cell population [34].…”

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

“…Sensitizing effect of Hsp90 inhibitor was demonstrated in many other transformed cells, the results of which are shown together with head and neck cancer cells in Table IX. (148) showed that the combination of GA with quercetin or KnK437 sensitized breast cancer stem-like cells characterized by high intracellular aldehyde dehydrogenase activity and higher expression of Hsp90α toward antiproliferation and anti-migration effects of GA. Lee et al (148) also found that knockdown of Hsp27 could mimic the effect of Hsp inhibitors to potentiate the breast cancer stem-like cell targeting effect of GA. Newman et al (149) also supported the use of Hsp90 inhibitor as a cancer stem cell targeting agent and showed, that HSF-1 is an important target for elimination of both cancer and non cancer stem cells in cancer. They found, that low concentrations of the Hsp90 inhibitor 17-AAG eliminate lymphoma cancer stem …”

Heat Shock Proteins Promote Cancer: It's a Protection Racket

“…In this case, the mechanism for CSC renewal involved another pathway, one involving the factor NFkB, a known factor in stemness[83]. Inhibition of Hsp90 also led to a reduction in stemness in a number of tumor types [84, 85] (Figure 4). Hsp90 is required for activity of the CSC renewal pathway involving the JAK-STAT system[86, 87].…”