Inhibition of p38-MK2 pathway enhances the efficacy of microtubule inhibitors in breast cancer cells.

IF 6.4 1区 生物学 Q1 BIOLOGY
eLife Pub Date : 2025-05-29 DOI:10.7554/eLife.104859
Yu-Chia Chen, Mamoru Takada, Aerica Nagornyuk, Muhan Yu, Hideyuki Yamada, Takeshi Nagashima, Masayuki Ohtsuka, Jennifer G DeLuca, Steven M Markus, Motoki Takaku, Aussie Suzuki
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引用次数: 0

Abstract

Microtubule-targeting agents (MTAs) are widely used as first- and second-line chemotherapies for various cancers. However, current MTAs exhibit positive responses only in subsets of patients and are often accompanied by side effects due to their impact on normal cells. This underscores an urgent need to develop novel therapeutic strategies that enhance MTA efficacy while minimizing toxicity to normal tissues. Here, we demonstrate that inhibition of the p38 MAPK-MK2 signaling pathway sensitizes cancer cells to MTA treatment. We utilize CMPD1, a dual-target inhibitor, to concurrently suppress the p38-MK2 pathway and microtubule dynamicity. In addition to its established role as an MK2 inhibitor, we find that CMPD1 rapidly induces microtubule depolymerization, preferentially at the microtubule plus end, leading to the inhibition of tumor growth and cancer cell invasion in both in vitro and in vivo models. Notably, 10 nM CMPD1 is sufficient to induce irreversible mitotic defects in cancer cells, but not in non-transformed normal cells, highlighting its high specificity to cancer cells. We further validate that a specific p38-MK2 inhibitor significantly potentiates the efficacy of subclinical concentrations of MTA. In summary, our findings suggest that the p38-MK2 pathway presents a promising therapeutic target in combination with MTAs in cancer treatment.

抑制p38-MK2通路可增强微管抑制剂在乳腺癌细胞中的作用。
微管靶向药物(mta)被广泛应用于各种癌症的一线和二线化疗。然而,目前的mta仅在部分患者中表现出积极反应,并且由于其对正常细胞的影响而经常伴有副作用。这强调了迫切需要开发新的治疗策略,以提高MTA的疗效,同时尽量减少对正常组织的毒性。在这里,我们证明抑制p38 MAPK-MK2信号通路使癌细胞对MTA治疗敏感。我们利用双靶点抑制剂CMPD1同时抑制p38-MK2通路和微管动力学。除了其作为MK2抑制剂的作用外,我们发现CMPD1快速诱导微管解聚,优先在微管+端,从而在体外和体内模型中抑制肿瘤生长和癌细胞侵袭。值得注意的是,10 nM的CMPD1足以在癌细胞中诱导不可逆的有丝分裂缺陷,但在未转化的正常细胞中却不能,这表明其对癌细胞的高特异性。我们进一步验证了特异性p38-MK2抑制剂显著增强亚临床浓度MTA的疗效。总之,我们的研究结果表明,p38-MK2途径与mta联合治疗癌症是一个有希望的治疗靶点。
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
eLife
eLife BIOLOGY-
CiteScore
12.90
自引率
3.90%
发文量
3122
审稿时长
17 weeks
期刊介绍: eLife is a distinguished, not-for-profit, peer-reviewed open access scientific journal that specializes in the fields of biomedical and life sciences. eLife is known for its selective publication process, which includes a variety of article types such as: Research Articles: Detailed reports of original research findings. Short Reports: Concise presentations of significant findings that do not warrant a full-length research article. Tools and Resources: Descriptions of new tools, technologies, or resources that facilitate scientific research. Research Advances: Brief reports on significant scientific advancements that have immediate implications for the field. Scientific Correspondence: Short communications that comment on or provide additional information related to published articles. Review Articles: Comprehensive overviews of a specific topic or field within the life sciences.
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