Dasatinib induces apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway in bladder cancer cells.

IF 2.5 3区医学 Q2 UROLOGY & NEPHROLOGY Investigative and Clinical Urology Pub Date : 2024-11-01 DOI:10.4111/icu.20240250

Jin-Nyoung Ho, Seok-Soo Byun, Danhyo Kim, Hoyoung Ryu, Sangchul Lee

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Abstract

Purpose: Bladder cancer is a common genitourinary malignant disease worldwide. Dasatinib is a small molecule inhibitor of Src family kinases. We investigated the anticancer effect and putative molecular mechanisms of dasatinib on T24 and cisplatin-resistant T24R2 human bladder cancer cells.

Materials and methods: Cell proliferation was measured using Cell Counting Kit-8 (CCK-8) and colony formation in dasatinib treated bladder cancer cells. Flow cytometry was used to determined cell cycle arrest and apoptosis. The expression of apoptosis and autophagy related proteins were detected by western blot analysis.

Results: In bladder cancer cells, dasatinib significantly reduced cell proliferation, colony formation, and induced G1-phase arrest. Dasatinib triggered apoptosis along with an increased expression of apoptosis-related genes (caspases, PARP, and cytochrome c). Down-regulation of Bcl-2 and up-regulation of Bad, which are hallmarks of apoptosis, were found to play a dominant role in mediating the effects of dasatinib treatment. We further showed that dasatinib inhibits p-Src, p-PI3K, p-Akt, and p-mTOR in bladder cancer cells. Dasatinib also increased the expression of markers of autophagy flux such as LC3-II and p62.

Conclusions: These results confirmed that dasatinib is a potent chemotherapeutic drug which induces apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway in bladder cancer cells.

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达沙替尼通过抑制膀胱癌细胞中的PI3K/Akt/mTOR通路诱导细胞凋亡和自噬。

目的：膀胱癌是全球常见的泌尿生殖系统恶性疾病。达沙替尼是一种小分子 Src 家族激酶抑制剂。我们研究了达沙替尼对T24和顺铂耐药的T24R2人膀胱癌细胞的抗癌作用和可能的分子机制：使用细胞计数试剂盒-8（CCK-8）测定达沙替尼处理的膀胱癌细胞的细胞增殖和集落形成。流式细胞术用于测定细胞周期停滞和细胞凋亡。结果表明，达沙替尼对膀胱癌细胞有抑制作用：结果：在膀胱癌细胞中，达沙替尼可明显减少细胞增殖和集落形成，并诱导细胞G1期停滞。达沙替尼可诱导细胞凋亡，同时增加凋亡相关基因（caspases、PARP和细胞色素c）的表达。研究发现，Bcl-2的下调和Bad的上调是细胞凋亡的标志，它们在达沙替尼治疗的效应中起着主导作用。我们进一步发现，达沙替尼抑制膀胱癌细胞中的p-Src、p-PI3K、p-Akt和p-mTOR。达沙替尼还增加了LC3-II和p62等自噬通量标志物的表达：这些结果证实达沙替尼是一种有效的化疗药物，它能通过抑制膀胱癌细胞的PI3K/Akt/mTOR通路诱导细胞凋亡和自噬。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Investigative and Clinical Urology Medicine-Urology

CiteScore

4.10

自引率

4.30%

发文量

审稿时长

4 weeks

期刊介绍： Investigative and Clinical Urology (Investig Clin Urol, ICUrology) is an international, peer-reviewed, platinum open access journal published bimonthly. ICUrology aims to provide outstanding scientific and clinical research articles, that will advance knowledge and understanding of urological diseases and current therapeutic treatments. ICUrology publishes Original Articles, Rapid Communications, Review Articles, Special Articles, Innovations in Urology, Editorials, and Letters to the Editor, with a focus on the following areas of expertise: • Precision Medicine in Urology • Urological Oncology • Robotics/Laparoscopy • Endourology/Urolithiasis • Lower Urinary Tract Dysfunction • Female Urology • Sexual Dysfunction/Infertility • Infection/Inflammation • Reconstruction/Transplantation • Geriatric Urology • Pediatric Urology • Basic/Translational Research One of the notable features of ICUrology is the application of multimedia platforms facilitating easy-to-access online video clips of newly developed surgical techniques from the journal''s website, by a QR (quick response) code located in the article, or via YouTube. ICUrology provides current and highly relevant knowledge to a broad audience at the cutting edge of urological research and clinical practice.