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Salinomycin suppresses T24 cells by regulating KDM1A and the unfolded protein response pathway
Haofeng Yuan1, Yiqian Li2, Yun Zou1
1Department of Urology, SSL Central Hospital of Dongguan City, No.1, Huangzhou Xianglong Road, Shilong Town, Dongguan, 523000 Guangdong China.
Abstract:
In recent years, salinomycin has been shown to exert an anticancer effect in a variety of tumors; however, its function and mechanism in bladder cancer (BC) remain unclear. This study examined the effect of salinomycin on bladder cancer and analyzed its regulatory mechanism. T24 cells were treated with different concentrations of salinomycin to detect subsequent changes in cell proliferation, apoptosis, oxidative stress, H3K4 methylation, and related gene expression by the CCK8 assay, Edu staining, Tunel staining, ELISA, RT-qPCR, and western blotting, respectively. A KDM1A overexpression plasmid, catalytically inactive KDM1A overexpression plasmid, or short hairpin RNA (shRNA) plasmid was transfected into T24 cells to evaluate their effects. A xenograft tumor model was used to further confirm the anti-tumor effect of salinomycin. Our results showed that salinomycin significantly inhibited cell proliferation, promoted apoptosis, increased MDA levels, decreased SOD levels, induced H3K4 histone methylation, and suppressed KDM1A expression. Furthermore, the sh-KDM1A plasmid had effects similar to those of salinomycin and also activated the unfolded protein response pathway. The KDM1A overexpression plasmid had effects opposite to those of the sh-KDM1A plasmid, and the catalytically inactive KDM1A overexpression plasmid had no effect. Meanwhile, KDM1A overexpression reversed the effects of salinomycin on T24 cells. Finally, in vivo experiments confirmed the above results. In the salinomycin treatment group, tumor growth and KDM1A expression were suppressed and cell apoptosis and UPR were induced, while treatment with the KDM1A overexpression plasmid produced the opposite effects. Collectively, our study revealed that salinomycin suppressed T24 cell proliferation and promoted oxidative stress and apoptosis by regulating KDM1A and the UPR pathway.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s10616-022-00546-y.
Insights
Salinomycin inhibits bladder cancer cell growth by promoting apoptosis and oxidative stress. It achieves this by downregulating KDM1A expression and activating the unfolded protein response (UPR) pathway.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Salinomycin exhibits anticancer properties across various tumors.
- The precise role and mechanism of salinomycin in bladder cancer (BC) remain largely unelucidated.
- Understanding these mechanisms is crucial for developing novel BC therapies.
Purpose of the Study:
- To investigate the anti-bladder cancer effects of salinomycin.
- To elucidate the regulatory mechanism of salinomycin in bladder cancer cells.
- To determine the role of KDM1A and the unfolded protein response (UPR) pathway in salinomycin's action.
Main Methods:
- Cell proliferation, apoptosis, and oxidative stress assays (CCK8, Edu, Tunel, ELISA).
- Analysis of H3K4 methylation and gene expression (RT-qPCR, Western Blotting).
- In vitro manipulation of KDM1A expression (overexpression plasmid, shRNA) and in vivo xenograft models.
Main Results:
- Salinomycin inhibited T24 cell proliferation, induced apoptosis, and promoted oxidative stress (increased MDA, decreased SOD).
- Salinomycin suppressed KDM1A expression and induced H3K4 histone methylation, activating the UPR pathway.
- KDM1A knockdown mimicked salinomycin's effects, while KDM1A overexpression reversed them, confirming KDM1A's central role.
Conclusions:
- Salinomycin exerts anti-bladder cancer effects by inhibiting proliferation and promoting apoptosis and oxidative stress.
- The mechanism involves the downregulation of KDM1A and subsequent activation of the UPR pathway.
- Targeting KDM1A and the UPR pathway represents a potential therapeutic strategy for bladder cancer.
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