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

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Abstract

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.

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Data availability

The data that support the findings of the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors express their gratitude to the Fujisaki Cell Center, Hayashibara Biochemical Laboratories, Inc. for providing the HUT-102 and MT-1 cells, Dr. Naoki Yamamoto (Tokyo Medical and Dental University) for providing the MT-2 and MT-4 cells, Dr. Masahiro Fujii (Niigata University) for providing the TL-OmI cells, and Dr. Diane Prager (UCLA School of Medicine) for providing the SLB-1 cells. We would also like to thank the University of the Ryukyus Center for Research Advancement and Collaboration, where the protein concentration assessments and flow cytometric analyses were performed. We would like to thank Editage (www.editage.com) for their assistance with English language editing.

Funding

This work was supported by the JSPS KAKENHI [Grant number 17K07175].

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Authors and Affiliations

  1. Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan

    Chie Ishikawa & Naoki Mori

  2. Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa, 903-0213, Japan

    Chie Ishikawa

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  1. Chie Ishikawa
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Contributions

All authors contributed to the study’s conception and design. Material preparation, data collection, experimental work, and analysis were performed by Chie Ishikawa and Naoki Mori. The first draft of the manuscript was written by Chie Ishikawa, and Naoki Mori commented on previous versions of the manuscript. All authors consented to the publication of this study.

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Correspondence to Naoki Mori.

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12032_2023_2042_MOESM1_ESM.tiff

Supplementary file1 Fig. S1. Effect of serum deprivation and KRIBB11 treatment on cell cycle progression and apoptosis of HTLV-1-infected T cells. Cell cycle analysis following PI staining of cells after 48 h culture in basal medium without serum. Following serum starvation, cells were cultured for 48 h in standard conditions with or without 12.5 μM KRIBB11. The results are shown as the mean values of the percentage of cells in G1 relative to the percentage in the S phase (a) and the mean values of the percentage of cells in the sub-G1 phase (b). Data are presented as mean ± SD from triplicate cultures. *P < 0.005, compared with control. (TIFF 10256 KB)

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Ishikawa, C., Mori, N. Heat shock factor 1 is a promising therapeutic target against adult T-cell leukemia. Med Oncol 40, 172 (2023). https://doi.org/10.1007/s12032-023-02042-5

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