Therapeutic protein PAK restrains the progression of triple negative breast cancer through degrading SREBP-1 mRNA

IF 6.1 1区 医学 Q1 ONCOLOGY Breast Cancer Research Pub Date : 2023-12-11 DOI:10.1186/s13058-023-01749-7
Pan Hu, Peiyi Zhou, Tieyun Sun, Dingkang Liu, Jun Yin, Lubin Liu
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Abstract

Triple-negative breast cancer (TNBC) represents the most challenging subtype of breast cancer. Studies have implicated an upregulation of lipid synthesis pathways in the initiation and progression of TNBC. Targeting lipid synthesis pathways may be a promising therapeutic strategy for TNBC. Our previous study developed a therapeutic protein PAK with passive targeting and inhibiting tumor proliferation. In this study, we further substantiate the efficacy of PAK in TNBC. Transcriptome sequencing analysis revealed PAK-mediated downregulation of genes involved in fatty acid synthesis, including key genes like SREBP-1, FASN, and SCD1. RNA immunoprecipitation experiments demonstrated a significant binding affinity of PAK to SREBP-1 mRNA, facilitating its degradation process. Both in vitro and in vivo models, PAK hampered TNBC progression by downregulating lipid synthesis pathways. In conclusion, this study emphasizes that PAK inhibits the progression of TNBC by binding to and degrading SREBP-1 mRNA, revealing a new strategy for regulating lipid synthesis in the intervention of TNBC and its therapeutic significance.
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治疗蛋白PAK通过降解SREBP-1 mRNA抑制三阴性乳腺癌的进展
三阴性乳腺癌(TNBC)是最具挑战性的乳腺癌亚型。研究表明,脂质合成途径的上调与 TNBC 的发生和发展有关。靶向脂质合成途径可能是治疗 TNBC 的一种有前景的策略。我们之前的研究开发了一种具有被动靶向性并能抑制肿瘤增殖的治疗性蛋白 PAK。在本研究中,我们进一步证实了PAK对TNBC的疗效。转录组测序分析显示,PAK介导了参与脂肪酸合成的基因下调,包括SREBP-1、FASN和SCD1等关键基因。RNA 免疫沉淀实验表明,PAK 与 SREBP-1 mRNA 有显著的结合亲和力,促进了其降解过程。在体外和体内模型中,PAK都通过下调脂质合成途径阻碍了TNBC的进展。总之,本研究强调了PAK通过与SREBP-1 mRNA结合并降解SREBP-1 mRNA来抑制TNBC的进展,揭示了一种在TNBC干预中调节脂质合成的新策略及其治疗意义。
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来源期刊
Breast Cancer Research
Breast Cancer Research 医学-肿瘤学
自引率
0.00%
发文量
76
期刊介绍: Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.
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