ACYP2通过促进parp1介导的DNA损伤修复诱导胶质母细胞瘤对替莫唑胺的耐药。

IF 4.7 2区 医学 Q2 CELL BIOLOGY
Mengjun Sui, Qing Cai, Zhiwei Sun, Jinjin Li, Yiyang Zhang, Mengdan Li, Penggao Dai, Gang Li
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引用次数: 0

摘要

多形性胶质母细胞瘤(GBM)是一种高度侵袭性的脑肿瘤,预后较差。替莫唑胺(TMZ)是使用最广泛的化疗药物,可显著提高患者的生存率。然而,许多患者出现TMZ耐药性,导致治疗效果有限。因此,研究TMZ在GBM患者中的耐药机制,确定TMZ的致敏靶点,对提高其临床疗效至关重要。在这里,我们证明了酰基磷酸酶2 (ACYP2)参与调节GBM对TMZ的敏感性。ACYP2敲低显著降低了GBM细胞中TMZ的IC50值,而ACYP2过表达使其IC50值升高。ACYP2敲除联合TMZ治疗不仅能抑制体外GBM细胞的恶性行为,还能减缓小鼠颅内GBM的进展。此外,彗星尾和γ-H2AX染色分析显示,ACYP2敲低增强了tmz诱导的DNA损伤。在机制上,ACYP2上调转录因子c-Myc,促进其下游靶点聚adp核糖聚合酶1 (PARP1)的转录,PARP1是DNA损伤修复的重要调控分子,最终诱导GBM细胞对TMZ的抗性。因此,本研究表明ACYP2是tmz耐药GBM患者的潜在治疗靶点。意义:acyp2驱动的c-Myc/PARP1信号轴定义了驱动替莫唑胺耐药的关键途径,并代表了胶质母细胞瘤治疗干预的翻译可操作靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ACYP2 induces temozolomide resistance in glioblastoma by promoting PARP1-mediated DNA damage repair.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor prognosis. Temozolomide (TMZ) is the most widely used chemotherapeutic agent and can significantly improve patient survival rates. However, numerous patients develop TMZ resistance, leading to limited therapeutic benefits. Therefore, it is crucial to investigate the mechanisms of TMZ resistance in patients with GBM and identify the sensitizing targets of TMZ to improve its clinical efficacy. Here, we demonstrated that acylphosphatase 2 (ACYP2) was involved in regulating the sensitivity of GBM to TMZ. ACYP2 knockdown significantly reduced the IC50 values of TMZ in GBM cells, while overexpression of ACYP2 increased their IC50 values. The combination of ACYP2 knockdown and TMZ treatment not only inhibited the malignant behavior of GBM cells in vitro but also slowed the progression of intracranial GBM in mice. Additionally, comet tail and γ-H2AX staining assays showed that ACYP2 knockdown enhanced the TMZ-induced DNA damage. Mechanistically, ACYP2 upregulates the transcription factor c-Myc to promote the transcription of its downstream target poly ADP-ribose polymerase 1 (PARP1), an important regulatory molecule for DNA damage repair, ultimately inducing TMZ resistance in GBM cells. Thus, this study demonstrated that ACYP2 is a potential therapeutic target for TMZ-resistant GBM patients. Implications: The ACYP2-driven c-Myc/PARP1 signaling axis defines a critical pathway driving temozolomide resistance and represents a translationally actionable target for therapeutic intervention in glioblastoma.

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来源期刊
Molecular Cancer Research
Molecular Cancer Research 医学-细胞生物学
CiteScore
9.90
自引率
0.00%
发文量
280
审稿时长
4-8 weeks
期刊介绍: Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.
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