TGF-β Enhances Doxorubicin Resistance and Anchorage-Independent Growth in Cancer Cells by Inducing ALDH1A1 Expression.

IF 5.7 2区医学 Q1 Medicine

Cancer Science Pub Date : 2025-05-25 DOI:10.1111/cas.70109

Takashi Yokoyama, Masao Saitoh, Keiji Miyazawa

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引用次数: 0

Abstract

The transforming growth factor-β (TGF-β)/Smad signaling pathway promotes malignant transformation through various mechanisms, and its effect on enhancing drug resistance can limit the efficacy of treatment. Here, we showed that pre-stimulation of human lung cancer A549 cells with TGF-β increases resistance to doxorubicin-induced growth inhibition in a Smad3- and Smad4-dependent manner. This effect was suppressed by the aldehyde dehydrogenase (ALDH) inhibitor oxyfedrine, suggesting that ALDH family members are involved in drug resistance. TGF-β upregulated the mRNA and protein expression of ALDH1A1. The TGF-β/Smad3 transcriptional enhancer region on ALDH1A1 was identified by Smad3 ChIP-seq analysis using an open database and by reporter assays. Knockdown of ALDH1A1 in A549 cells suppressed TGF-β-induced doxorubicin resistance, and lentivirus-mediated introduction of ALDH1A1 into A549 SMAD3-KO cells restored drug resistance. We also demonstrated that ALDH1A1 is required and sufficient for TGF-β/Smad3 signaling-induced anchorage-independent growth. The results suggest that the TGF-β/Smad3/4 axis promotes resistance to doxorubicin and anchorage-independent growth by inducing the transcription of ALDH1A1.

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TGF-β通过诱导ALDH1A1表达增强肿瘤细胞阿霉素耐药和非锚定生长

转化生长因子-β (TGF-β)/Smad信号通路通过多种机制促进恶性转化，其增强耐药的作用可能限制治疗效果。在这里，我们发现用TGF-β预刺激人肺癌A549细胞以Smad3-和smad4依赖的方式增加对阿霉素诱导的生长抑制的抗性。这种作用被醛脱氢酶（ALDH）抑制剂氧fedrine抑制，提示ALDH家族成员参与了耐药性。TGF-β上调ALDH1A1 mRNA和蛋白表达。ALDH1A1上的TGF-β/Smad3转录增强子区域通过Smad3 ChIP-seq分析，利用开放数据库和报告基因分析确定。A549细胞中ALDH1A1的下调可抑制TGF-β诱导的阿霉素耐药，慢病毒介导的ALDH1A1导入A549 SMAD3-KO细胞可恢复耐药。我们还证明了ALDH1A1对于TGF-β/Smad3信号诱导的非锚定依赖性生长是必需的和充分的。结果表明，TGF-β/Smad3/4轴通过诱导ALDH1A1的转录促进对阿霉素的抗性和锚定非依赖性生长。

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

Cancer Science ONCOLOGY-

CiteScore

9.90

自引率

3.50%

发文量

406

审稿时长

17 weeks

期刊介绍： Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.