O-GlcNAcylation inhibition redirects the response of colon cancer cells to chemotherapy from senescence to apoptosis.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Ingrid Loison, Adrien Pioger, Sonia Paget, Inès Metatla, Audrey Vincent, Corinne Abbadie, Vanessa Dehennaut
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Abstract

The potential use of pro-senescence therapies, known as TIS (Therapy-Induced Senescence), for the treatment of colorectal cancer (CRC) generated significant interest since they require lower doses compared to those required for inducing apoptosis. However, the senescent cell cycle-arrested cancer cells are long-lived, and studies have revealed escape mechanisms contributing to tumor recurrence. To deepen our understanding of the survival pathways used by senescent cancer cells, we delved into the potential involvement of the hexosamine biosynthetic pathway (HBP). HBP provides UDP-GlcNAc, the substrate for O-GlcNAc transferase (OGT), which catalyzes O-GlcNAcylation, a post-translational modification implicated in regulating numerous cellular functions and aberrantly elevated in CRC. In this study, we demonstrated, in the p53-proficient colon cancer cell lines HCT116 and LS174T, that TIS induced by low-dose SN38 or etoposide treatment was accompanied with a decrease of GFAT (the rate limiting enzyme of the HBP), OGT and O-GlcNAcase (OGA) expression correlated with a slight reduction in O-GlcNAcylation levels. Further decreasing this level of O-GlcNAcylation by knocking-down GFAT or OGT redirected the cellular response to subtoxic chemotherapy doses from senescence to apoptosis, in correlation with an enhancement of DNA damages. Pharmacological inhibition of OGT with OSMI-4 in HCT116 and LS174T cells and in a patient-derived colon tumoroid model supported these findings. Taken together, these results suggest that combing O-GlcNAcylation inhibitors to low doses of conventional chemotherapeutic drugs could potentially reduce treatment side effects while preserving efficacy. Furthermore, this approach may increase treatment specificity, as CRC cells exhibit higher O-GlcNAcylation levels compared to normal tissues.

抑制 O-GlcNAcylation 可使结肠癌细胞对化疗的反应从衰老转向凋亡。
治疗诱导衰老疗法(TIS)可能用于治疗结直肠癌(CRC),这引起了人们的极大兴趣,因为与诱导细胞凋亡相比,这种疗法所需的剂量更低。然而,衰老细胞周期停滞的癌细胞寿命很长,研究发现了导致肿瘤复发的逃逸机制。为了加深对衰老癌细胞生存途径的了解,我们深入研究了六聚糖生物合成途径(HBP)的潜在参与。HBP为O-GlcNAc转移酶(OGT)提供底物UDP-GlcNAc,OGT催化O-GlcNAcylation,O-GlcNAcylation是一种翻译后修饰,与调节多种细胞功能有关,在CRC中异常升高。在这项研究中,我们在具有 p53 缺陷的结肠癌细胞系 HCT116 和 LS174T 中证实,低剂量 SN38 或依托泊苷治疗诱导的 TIS 会导致 GFAT(HBP 的限速酶)、OGT 和 O-GlcNA 酶(OGA)表达的减少,这与 O-GlcNAcylation 水平的轻微降低有关。通过敲除 GFAT 或 OGT 进一步降低 O-GlcNAcylation 水平,可使细胞对亚毒性化疗剂量的反应从衰老转向凋亡,这与 DNA 损伤的增加有关。在 HCT116 和 LS174T 细胞中以及在源自患者的结肠肿瘤模型中使用 OSMI-4 对 OGT 进行药理抑制也证实了这些发现。综上所述,这些结果表明,将 O-GlcNAcylation 抑制剂与低剂量的传统化疗药物相结合,有可能在保持疗效的同时减少治疗副作用。此外,这种方法可能会提高治疗的特异性,因为与正常组织相比,CRC 细胞表现出更高的 O-GlcNAcylation 水平。
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
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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