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选择性靶向 IRAK1 可减弱低分子量透明质酸诱导的上皮性卵巢癌细胞干性和非经典 STAT3 激活。

Selective targeting of IRAK1 attenuates low molecular weight hyaluronic acid-induced stemness and non-canonical STAT3 activation in epithelial ovarian cancer.

机构信息

Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.

Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA.

出版信息

Cell Death Dis. 2024 May 25;15(5):362. doi: 10.1038/s41419-024-06717-3.

DOI:10.1038/s41419-024-06717-3
PMID:38796478
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11127949/
Abstract

Advanced epithelial ovarian cancer (EOC) survival rates are dishearteningly low, with ~25% surviving beyond 5 years. Evidence suggests that cancer stem cells contribute to acquired chemoresistance and tumor recurrence. Here, we show that IRAK1 is upregulated in EOC tissues, and enhanced expression correlates with poorer overall survival. Moreover, low molecular weight hyaluronic acid, which is abundant in malignant ascites from patients with advanced EOC, induced IRAK1 phosphorylation leading to STAT3 activation and enhanced spheroid formation. Knockdown of IRAK1 impaired tumor growth in peritoneal disease models, and impaired HA-induced spheroid growth and STAT3 phosphorylation. Finally, we determined that TCS2210, a known inducer of neuronal differentiation in mesenchymal stem cells, is a selective inhibitor of IRAK1. TCS2210 significantly inhibited EOC growth in vitro and in vivo both as monotherapy, and in combination with cisplatin. Collectively, these data demonstrate IRAK1 as a druggable target for EOC.

摘要

高级上皮性卵巢癌 (EOC) 的生存率令人沮丧地低，只有约 25%的患者能存活 5 年以上。有证据表明，癌症干细胞有助于获得性化疗耐药和肿瘤复发。在这里，我们表明 IRAK1 在 EOC 组织中上调，并且增强的表达与总生存率降低相关。此外，在患有晚期 EOC 的患者的恶性腹水中大量存在的低分子量透明质酸诱导 IRAK1 磷酸化，导致 STAT3 激活和增强球体形成。IRAK1 的敲低可损害腹膜疾病模型中的肿瘤生长，并损害 HA 诱导的球体生长和 STAT3 磷酸化。最后，我们确定 TCS2210，一种已知的间充质干细胞中神经元分化的诱导剂，是 IRAK1 的选择性抑制剂。TCS2210 作为单一疗法和与顺铂联合使用，均可显著抑制体外和体内的 EOC 生长。总的来说，这些数据表明 IRAK1 是 EOC 的一个可用药靶。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/9f3347005f7b/41419_2024_6717_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/4402ddda49fb/41419_2024_6717_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/1027e12cc3da/41419_2024_6717_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/aa6a58a76ac0/41419_2024_6717_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/ef19110e5a9f/41419_2024_6717_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/93c905f5ccc8/41419_2024_6717_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/9f3347005f7b/41419_2024_6717_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/4402ddda49fb/41419_2024_6717_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/1027e12cc3da/41419_2024_6717_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/aa6a58a76ac0/41419_2024_6717_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/ef19110e5a9f/41419_2024_6717_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/93c905f5ccc8/41419_2024_6717_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b43/11127949/9f3347005f7b/41419_2024_6717_Fig6_HTML.jpg

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Deregulated hyaluronan metabolism in the tumor microenvironment drives cancer inflammation and tumor-associated immune suppression.肿瘤微环境中透明质酸代谢失调可导致癌症炎症和肿瘤相关免疫抑制。
Front Immunol. 2022 Sep 27;13:971278. doi: 10.3389/fimmu.2022.971278. eCollection 2022.
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The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC.
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Etiopathogenesis of ovarian cancer. An inflamm-aging entity?卵巢癌的病因发病机制。一种炎性衰老实体？
Gynecol Oncol Rep. 2022 Jun 11;42:101018. doi: 10.1016/j.gore.2022.101018. eCollection 2022 Aug.
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