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Suppression of TBCK enhances TRAIL-mediated apoptosis by causing the inactivation of the akt signaling pathway in human renal carcinoma Caki-1 cells

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Abstract

Background

TBC1 domain-containing kinase (TBCK) protein functions as a growth suppressor in certain cell types and as a tumor promoter in others. Although TBCK knockdown increases the responsiveness of cancer cells to anticancer drugs, the detailed mechanisms by which TBCK knockdown increases susceptibility to anticancer drugs remain unknown.

Objective

This study analyzed the role of TBCK in sensitivities to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and doxorubicin in human renal cancer cells.

Methods

Flow cytometry was employed to evaluate the extent of apoptosis. Western blotting, transient transfection, and lentiviral infection techniques were conducted to investigate the impact of TBCK on apoptosis-related protein expression and mitogen-activated protein kinase (MAPK).

Results

TBCK knockdown in renal cancer cells inhibits ERK and Akt signaling pathways and increases TRAIL and doxorubicin sensitivity. In TBCK-knockdown Caki-1 cells, ERK and Akt phosphorylation was suppressed compared to control cell lines, and TRAIL and doxorubicin sensitivities were increased in these cells. In addition, the phosphorylation of PDK1 was suppressed in TBCK-suppressed cells, indicating that TBCK may be involved in the PDK1 and Akt signaling pathways. The introduction of dominantly active Akt into TBCK-suppressed cells restored their sensitivity to TRAIL. In addition, TBCK downregulation enhanced TRAIL sensitivity in different renal cancer cell lines.

Conclusions

These data suggest that TBCK could potentially have a crucial function in influencing the effects of anti-cancer drugs including TRAIL by modulating the signaling pathway involving Akt and PDK1 in human renal cancer cells.

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Funding

This work was supported by the Basic Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (NRF-2020R1F1A1048259).

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Author notes

  1. Cho-Young Park and Ji-Hoon Jang contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy, College of Medicine, Yeungnam University, 170 Hyeonchung-ro, Nam-Gu, Daegu, 705- 717, Korea

    Cho-Young Park, Ji-Hoon Jang, In-Hwan Song, Joo-Young Kim & Tae-Jin Lee

  2. Department of Physiology, College of Medicine, Yeungnam University, 170 Hyeonchung-ro, Nam-Gu, Daegu, 705-717, Korea

    Kyung-Oh Doh

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  1. Cho-Young Park
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  2. Ji-Hoon Jang
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  5. Kyung-Oh Doh
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Correspondence to Tae-Jin Lee.

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Park, CY., Jang, JH., Song, IH. et al. Suppression of TBCK enhances TRAIL-mediated apoptosis by causing the inactivation of the akt signaling pathway in human renal carcinoma Caki-1 cells. Genes Genom 45, 1357–1365 (2023). https://doi.org/10.1007/s13258-023-01453-y

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  • DOI: https://doi.org/10.1007/s13258-023-01453-y

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