菊花素通过抑制cGAS-STING通路减轻乳腺癌治疗性衰老。

IF 3.5 4区 医学 Q2 ONCOLOGY
Rezina Billimoria, Purvi Bhatt
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引用次数: 0

摘要

乳腺癌仍然是全球妇女癌症相关死亡的主要原因,细胞衰老在其进展中起着复杂的作用。衰老通过衰老相关分泌表型(SASP)与慢性炎症有关。由组蛋白修饰(H3K27me3和H3K9me3)标记的细胞质染色质片段(CCFs)激活的环鸟苷单磷酸-腺苷单磷酸(cGMP-AMP)合成酶(cGAS)-干扰素基因刺激因子(STING)通路对SASP的产生至关重要。本研究探讨了天然黄酮类化合物菊花素的潜力,作为一种同源性药物,靶向这些CCF标记物,以减少衰老乳腺癌细胞的炎症。我们用多柔比星诱导MDA-MB-231和MCF-7细胞衰老,并通过qRT-PCR分析不同浓度黄霉素处理后炎症因子IL-6和IL-8的表达水平。Western blotting和免疫荧光显示CCF标记物H3K9me3和H3K27me3显著降低,STING磷酸化降低。值得注意的是,Chrysin没有改变衰老标志物p16和p21的表达。此外,Chrysin有效抑制sasp驱动的乳腺癌细胞侵袭和集落形成,突出了其作为抗炎剂和致形药物的潜力。Chrysin显著降低H3K9me3和h3k27me3标记的CCF水平,抑制cGAS-STING通路激活,降低IL-6和IL-8水平。我们的研究结果表明,菊花素是一种很有前景的治疗策略,它可以靶向CCFs的表观遗传景观,调节SASP以减轻衰老细胞在肿瘤微环境中的有害影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Chrysin mitigates therapy-induced senescence in breast cancer via cGAS-STING pathway inhibition.

Breast cancer continues to be a leading cause of cancer-related deaths among women globally, with cellular senescence having a complex role in its progression. Senescence is linked to chronic inflammation via the senescence-associated secretory phenotype (SASP). The cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway, activated by cytoplasmic chromatin fragments (CCFs) marked by histone modifications (H3K27me3 and H3K9me3), is crucial for SASP production. This study investigates the potential of a natural flavonoid, Chrysin, as a senomorphic agent that targets these CCF markers to reduce inflammation in senescent breast cancer cells. We induced senescence in MDA-MB-231 and MCF-7 cells using doxorubicin and analyzed the expression levels of inflammatory cytokines IL-6 and IL-8 after treatment with various concentrations of Chrysin through qRT-PCR. Western blotting and immunofluorescence revealed significantly reduced CCF markers H3K9me3 and H3K27me3, along with decreased STING phosphorylation. Notably, Chrysin did not change the expression of senescent markers p16 or p21. Additionally, Chrysin effectively inhibited SASP-driven breast cancer cell invasion and colony formation, highlighting its potential as both an anti-inflammatory agent and a senomorphic drug. Chrysin notably decreases H3K9me3 and H3K27me3-marked CCF levels, suppressing cGAS-STING pathway activation and reducing IL-6 and IL-8 levels. Our findings indicate that Chrysin represents a promising therapeutic strategy, targeting the epigenetic landscape of CCFs and modulating the SASP to mitigate the harmful effects of senescent cells in the tumor microenvironment.

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来源期刊
Medical Oncology
Medical Oncology 医学-肿瘤学
CiteScore
4.20
自引率
2.90%
发文量
259
审稿时长
1.4 months
期刊介绍: Medical Oncology (MO) communicates the results of clinical and experimental research in oncology and hematology, particularly experimental therapeutics within the fields of immunotherapy and chemotherapy. It also provides state-of-the-art reviews on clinical and experimental therapies. Topics covered include immunobiology, pathogenesis, and treatment of malignant tumors.
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