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B7-H3 通过 AKT/TM4SF1/SIRT1 通路抑制阿霉素诱导的结直肠癌细胞衰老样生长停滞。

B7-H3 suppresses doxorubicin-induced senescence-like growth arrest in colorectal cancer through the AKT/TM4SF1/SIRT1 pathway.

机构信息

Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China.

Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China.

出版信息

Cell Death Dis. 2021 May 6;12(5):453. doi: 10.1038/s41419-021-03736-2.

DOI:10.1038/s41419-021-03736-2
PMID:33958586
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8102521/
Abstract

Emerging evidence suggests that cellular senescence induced by chemotherapy has been recognized as a new weapon for cancer therapy. This study aimed to research novel functions of B7-H3 in cellular senescence induced by a low dose of doxorubicin (DOX) in colorectal cancer (CRC). Here, our results demonstrated that B7-H3 knockdown promoted, while B7-H3 overexpression inhibited, DOX-induced cellular senescence. B7-H3 knockdown dramatically enhanced the growth arrest of CRC cells after low-dose DOX treatment, but B7-H3 overexpression had the opposite effect. By RNA-seq analysis and western blot, we showed that B7-H3 prevented cellular senescence and growth arrest through the AKT/TM4SF1/SIRT1 pathway. Blocking the AKT/TM4SF1/SIRT1 pathway dramatically reversed B7-H3-induced resistance to cellular senescence. More importantly, B7-H3 inhibited DOX-induced cellular senescence of CRC cells in vivo. Therefore, targeting B7-H3 or the B7-H3/AKT/TM4SF1/SIRT1 pathway might be a new strategy for promoting cellular senescence-like growth arrest during drug treatment in CRC.

摘要

新出现的证据表明，化疗诱导的细胞衰老已被认为是癌症治疗的新武器。本研究旨在研究低剂量阿霉素（DOX）诱导的结直肠癌细胞（CRC）衰老中 B7-H3 的新功能。在这里，我们的结果表明，B7-H3 敲低促进，而 B7-H3 过表达抑制 DOX 诱导的细胞衰老。B7-H3 敲低显著增强了 CRC 细胞在低剂量 DOX 处理后的生长停滞，但 B7-H3 过表达则产生相反的效果。通过 RNA-seq 分析和 Western blot，我们表明 B7-H3 通过 AKT/TM4SF1/SIRT1 通路防止细胞衰老和生长停滞。阻断 AKT/TM4SF1/SIRT1 通路可显著逆转 B7-H3 诱导的对细胞衰老的耐药性。更重要的是，B7-H3 抑制了 DOX 诱导的 CRC 细胞体内的细胞衰老。因此，靶向 B7-H3 或 B7-H3/AKT/TM4SF1/SIRT1 通路可能是在 CRC 药物治疗期间促进类似细胞衰老的生长停滞的新策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/35a8eb045944/41419_2021_3736_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/f1f1a7f37751/41419_2021_3736_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/5316ced354ab/41419_2021_3736_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/f8c4eacac332/41419_2021_3736_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/a43b8e7b33c9/41419_2021_3736_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/5dffa11b0d10/41419_2021_3736_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/94653f1b46c6/41419_2021_3736_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/3ab5a8ca52a6/41419_2021_3736_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/35a8eb045944/41419_2021_3736_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/f1f1a7f37751/41419_2021_3736_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/5316ced354ab/41419_2021_3736_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/f8c4eacac332/41419_2021_3736_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/a43b8e7b33c9/41419_2021_3736_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/5dffa11b0d10/41419_2021_3736_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/94653f1b46c6/41419_2021_3736_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/3ab5a8ca52a6/41419_2021_3736_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f1/8102521/35a8eb045944/41419_2021_3736_Fig8_HTML.jpg

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