Heat shock factor 1 is a promising therapeutic target against adult T-cell leukemia

by Selleckchem | Nov 18 2023

Patients with adult T-cell leukemia (ATL), which is caused by human T-cell leukemia virus type 1 (HTLV-1), show poor prognosis because of drug resistance. Heat shock protein (HSP) 90 is reportedly essential for ATL cell survival as it regulates important signaling pathways, thereby making HSP90 inhibitors new therapeutic candidates for ATL. However, HSP90 inhibition increases the expression of other HSPs, suggesting that HSPs may contribute to drug resistance. The heat shock factor 1 (HSF1) transcription factor is the primary regulator of the expression of HSPs. Furthermore, targeting HSF1 disrupts the HSP90 chaperone function. Herein, we demonstrated that HSF1 is overexpressed in HTLV-1-infected T cells. HSF1 knockdown inhibited the proliferation of HTLV-1-infected T cells. HSF1 inhibitor KRIBB11 reduced the expression and phosphorylation of HSF1, downregulated HSP70 and HSP27 expression, and suppressed Akt, nuclear factor-κB, and AP-1 signals. KRIBB11 treatment induced DNA damage, upregulated p53 and p21, and reduced the expression of cyclin D2/E, CDK2/4, c-Myc, MDM2, and β-catenin, thereby preventing retinoblastoma protein phosphorylation and inhibiting G1-S cell cycle progression. KRIBB11 also induced caspase-mediated apoptosis concomitant with the suppression of Bcl-xL, Mcl-1, XIAP, c-IAP1/2, and survivin expression. KRIBB11 inhibited HSP70 and HSP90 upregulation through treatment with AUY922, an HSP90 inhibitor, and enhanced the cytotoxic effect of AUY922, suggesting a salvage role of HSF1-dependent HSP induction in response to drug treatment. Finally, treatment of mice with KRIBB11 reduced ATL tumor growth. Therefore, this study provides a strong rationale to target HSF1 and validates the anti-ATL activity of KRIBB11.

Comments:

The research findings you've shared indicate that targeting the heat shock factor 1 (HSF1) transcription factor using the inhibitor KRIBB11 has potential therapeutic benefits in the context of adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1). Here's a summary of the key points from the study:

1. **Background:**
   - ATL is caused by HTLV-1 and is known for poor prognosis due to drug resistance.
   - Heat shock protein 90 (HSP90) is vital for ATL cell survival and is a target for therapy.
   - HSP90 inhibition leads to increased expression of other heat shock proteins (HSPs), potentially contributing to drug resistance.

2. **HSF1 Overexpression in HTLV-1-Infected T Cells:**
- HSF1, the regulator of HSP expression, is overexpressed in HTLV-1-infected T cells.

3. **HSF1 Inhibition Effects:**
   - HSF1 knockdown hindered the proliferation of HTLV-1-infected T cells.
   - The HSF1 inhibitor KRIBB11 reduced HSF1 expression and phosphorylation.
   - KRIBB11 downregulated HSP70 and HSP27 expression and suppressed multiple signaling pathways (Akt, nuclear factor-κB, AP-1).
   - KRIBB11 induced DNA damage, upregulated p53 and p21, and inhibited cell cycle progression and key proteins related to cell cycle regulation.

4. **Apoptosis Induction:**
- KRIBB11 induced caspase-mediated apoptosis.
- It reduced the expression of anti-apoptotic proteins (Bcl-xL, Mcl-1, XIAP, c-IAP1/2, survivin).

5. **Synergy with HSP90 Inhibitor (AUY922):**
- KRIBB11 inhibited the upregulation of HSP70 and HSP90 induced by AUY922.
- Enhanced the cytotoxic effect of AUY922, indicating a potential role in overcoming drug resistance.

6. **In Vivo Efficacy:**
- In mice, KRIBB11 treatment reduced ATL tumor growth, validating its potential as a therapeutic agent.

In summary, this study suggests that targeting HSF1 with KRIBB11 has promising anti-ATL effects. By inhibiting HSF1, KRIBB11 disrupts multiple pathways essential for ATL cell survival, induces apoptosis, and sensitizes cells to HSP90 inhibition. These findings provide a strong rationale for further exploration of HSF1 inhibitors as a potential treatment strategy for ATL, particularly in cases resistant to current therapies.