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转化生长因子-β通过诱导醛脱氢酶1A1表达增强癌细胞对阿霉素的耐药性及非锚定依赖性生长。

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

作者信息

Yokoyama Takashi, Saitoh Masao, Miyazawa Keiji

机构信息

Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Chuo, Japan.

Center for Medical Education and Sciences, Graduate School of Medicine, University of Yamanashi, Chuo, Japan.

出版信息

Cancer Sci. 2025 Aug;116(8):2176-2188. doi: 10.1111/cas.70109. Epub 2025 May 25.

DOI:10.1111/cas.70109
PMID:40414259
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12317391/
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.

摘要

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，其增强耐药性的作用会限制治疗效果。在此，我们表明用TGF-β预刺激人肺癌A549细胞会以Smad3和Smad4依赖的方式增加对阿霉素诱导的生长抑制的抗性。醛脱氢酶（ALDH）抑制剂奥昔非君可抑制这种作用，表明ALDH家族成员参与耐药性。TGF-β上调了ALDH1A1的mRNA和蛋白表达。通过使用开放数据库的Smad3染色质免疫沉淀测序（ChIP-seq）分析和报告基因检测确定了ALDH1A1上的TGF-β/Smad3转录增强子区域。敲低A549细胞中的ALDH1A1可抑制TGF-β诱导的阿霉素抗性，而慢病毒介导的将ALDH1A1导入A549 SMAD3基因敲除细胞可恢复耐药性。我们还证明，ALDH1A1对于TGF-β/Smad3信号诱导的非锚定依赖性生长是必需的且足够的。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非锚定依赖性生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/31d585ae9fe1/CAS-116-2176-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/2ffefd74a375/CAS-116-2176-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/a63c0655078b/CAS-116-2176-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/5680ea5473aa/CAS-116-2176-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/5191d2161be7/CAS-116-2176-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/1421bf00105b/CAS-116-2176-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/31d585ae9fe1/CAS-116-2176-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/2ffefd74a375/CAS-116-2176-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/a63c0655078b/CAS-116-2176-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/5680ea5473aa/CAS-116-2176-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/5191d2161be7/CAS-116-2176-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/1421bf00105b/CAS-116-2176-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/933b/12317391/31d585ae9fe1/CAS-116-2176-g005.jpg

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