Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

FOXN3 attenuates doxorubicin resistance of bladder urothelial carcinoma via SIRT6/PI3K/AKT/mTOR pathway

Yinan Han¹, Shengxing Wang² , Rurui Xia², Jinhuo Chen², Bangfen Zhou²

¹Operation Room, The Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570102, China; ²Department of Urology, The Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570102, China.

For correspondence:- Shengxing Wang Email: wangshengxing_ff25@126.com Tel:+8689866528026

Accepted: 28 October 2022 Published: 30 November 2022

Citation: Han Y, Wang S, Xia R, Chen J, Zhou B. FOXN3 attenuates doxorubicin resistance of bladder urothelial carcinoma via SIRT6/PI3K/AKT/mTOR pathway. Trop J Pharm Res 2022; 21(11):2323-2330 doi: 10.4314/tjpr.v21i11.8

© 2022 The authors.
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Abstract

Purpose: To investigate the effect of forkhead box N3 (FOXN3) protein on doxorubicin (DOX) resistance of urothelial carcinoma (BLCA).

Methods: Bioinformatics prediction and immunoblotting were used to evaluate FOXN3 expression in BLCA tissues and cells. The FOXN3 overexpression was achieved by cell transfection. The effects of FOXN3 on DOX resistance and cell apoptosis were determined by immunoblotting, DOX resistance assay, and flow cytometry, while immunoblotting was applied to evaluate SIRT6/PI3K/AKT/mTOR signaling activity. Finally, SIRT6 overexpression and exogenous addition of a PI3K/AKT activator were used to investigate the molecular mechanism by which FOXN3 regulates DOX resistance phenotype.

Results: The FOXN3 was downregulated in DOX-resistant BLCA tissues and cells while its overexpression attenuated doxorubicin resistance (p < 0.01). Furthermore, apoptotic cell ratio increased from 7.54 to 26.83 % in J82/DOX cells and from 6.31 to 17.89 % in T24/DOX cells (p < 0.01) after FOXN3 overexpression. Moreover, FOXN3 upregulation inhibited sirtuin 6 (SIRT6) expression and inactivated PI3K/AKT/mTOR signaling pathway. Both SIRT6 overexpression and PI3K/AKT activation abrogated the FOXN3-mediated inhibition of DOX resistance in BLCA cells.

Conclusion: The FOXN3 attenuates the DOX resistance of BLCA through SIRT6/PI3K/AKT/mTOR pathway, thus providing a promising therapeutic strategy for the management of BLCA.

Keywords: Forkhead Box N3, Doxorubicin resistance, Bladder urothelial carcinoma, Sirtuin 6