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Blockade of integrin signaling reduces chemotherapy-induced premature senescence in collagen cultured bladder cancer cells.

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机构： [1]National Clinical Research Center of Geriatrics, the Center of Gerontology and Geriatrics,West China Hospital, Sichuan University, Chengdu 610041, China [2]Department of Urology, Institute of Urology and National Clinical Research Center for Geriatrics,West China Hospital, Sichuan University, Chengdu 610041, China [3]West China School of Medicine, Sichuan University, Chengdu 610041, China [4]Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu 610065, China [5]Department of Molecular Oncology, Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland

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关键词： premature senescence integrins bladder cancer chemotherapy collagen

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Diminished sensitivity towards chemotherapy remains the major impediment to the clinical treatment of bladder cancer. However, the critical elements in control of chemotherapy resistance remain obscure.We adopted improved collagen gels and performed cytotoxicity analysis of doxorubicin (DOX) and mitomycin C (MMC) of bladder cancer cells in a 3D culture system. We then detected the expression of multidrug resistant gene ABCB1, dormancy-associated functional protein chicken ovalbumin upstream-transcription factor 1 (COUPTF1), cell proliferation marker Ki-67, and cellular senescence marker senescence-associated β-galactosidase (SA-β-Gal) in these cells. We further tested the effects of integrin blockade or protein kinase B (AKT) inhibitor on the senescent state of bladder cancer. Also, we examined the tumor growth and survival time of bladder cancer mouse models given the combination treatment of chemotherapeutic agents and integrin α2β1 ligand peptide TFA (TFA).Collagen gels played a repressive role in bladder cancer cell apoptosis induced by DOX and MMC. In mechanism, collagen activated the integrin β1/AKT cascade to drive bladder cancer cells into a premature senescence state via the p21/p53 pathway, thus attenuating chemotherapy-induced apoptosis. In addition, TFA had the ability to mediate the switch from senescence to apoptosis of bladder cancer cells in xenograft mice. Meanwhile, TFA combined with chemotherapeutic drugs produced a substantial suppression of tumor growth as well as an extension of survival time in vivo.Based on our finding that integrin β1/AKT acted primarily to impart premature senescence to bladder cancer cells cultured in collagen gel, we suggest that integrin β1 might be a feasible target for bladder cancer eradication.© The Author(s) 2022. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University.

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出版当年[2022]版：

大类 | 4 区医学

小类 | 4 区医学：研究与实验

最新[2023]版：

大类 | 4 区医学

小类 | 4 区医学：研究与实验

第一作者：

第一作者机构： [1]National Clinical Research Center of Geriatrics, the Center of Gerontology and Geriatrics,West China Hospital, Sichuan University, Chengdu 610041, China

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通讯机构： [1]National Clinical Research Center of Geriatrics, the Center of Gerontology and Geriatrics,West China Hospital, Sichuan University, Chengdu 610041, China [2]Department of Urology, Institute of Urology and National Clinical Research Center for Geriatrics,West China Hospital, Sichuan University, Chengdu 610041, China [5]Department of Molecular Oncology, Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland

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Blockade of integrin signaling reduces chemotherapy-induced premature senescence in collagen cultured bladder cancer cells.

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