Oncogenic GALNT5 confers FOLFIRINOX resistance via activating the MYH9/ NOTCH/ DDR axis in pancreatic ductal adenocarcinoma.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-10-21 DOI:10.1038/s41419-024-07110-w
Qinyuan Jia, Yuheng Zhu, Hongfei Yao, Yifan Yin, Zonghao Duan, Jiahao Zheng, Ding Ma, Minwei Yang, Jianyu Yang, Junfeng Zhang, Dejun Liu, Rong Hua, Yanmiao Huo, Xueliang Fu, Yongwei Sun, Wei Liu
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Abstract

Chemotherapy resistance has been a great challenge in pancreatic ductal adenocarcinoma(PDAC) treatments. Current first-line chemotherapy regimens for PDAC include gemcitabine-based regimens such as AG regimen (albumin paclitaxel and gemcitabine), fluorouracil-based regiments such as FOLFIRINOX regimen ((5-fluorouracil5-FU), oxaliplatin, Irinotecan) and platinum-based regimens for patients with BRCA mutations. large amounts of work have been done on exploring the mechanism underlying resistance of gemcitabine-based and platinum-based regimens, while little research has been achieved on the mechanism of FOLFIRINOX regimens resistance. Hence, we identified Polypeptide N-Acetylgalactosaminyltransferase 5, (GALNT5) as a vital regulator and a potential therapeutic target in FOLFIRINOX regimens resistance. Colony formation assays and flow cytometry assays were performed to explore the roles of GALNT5 in cell proliferation and apoptosis in PDAC treated with FOLFIRINOX. IC50 alterations were calculated in GALNT5 knockdown and overexpressed cell lines. RNA-seq followed by GSEA (gene set enrichment analysis) was displayed to explore the potential mechanism. WB (western blotting), real-time PCR, and IF (immunofluorescence) were performed to validate relative pathways. The mouse orthotopic xenograft PDAC model was established to examine GALNT5 functions in vivo. GALNT5 was highly expressed in PDAC tissues and predicted poor prognosis in PDAC. Upregulation of GALNT5 in PDAC cells conferred FOLFIRINOX resistance on PDAC by inhibiting DNA damage. Moreover, GALNT5 interacted with MYH9, thus participating in the activation of the NOTCH pathways, resulting in hampering FOI-induced DNA damage. Functions of GALNT5 promoting FOLFIRINOX resistance were validated in vivo. In this study, we found that aberrantly overexpressed GALNT5 in PDAC took part in the activation of the NOTCH pathway by interacting with MYH9, thus inhibiting the DDR to achieve FOLFIRINOX resistance and causing poor prognosis. We identified GALNT5 as a potential therapeutic target for PDAC patients resistant to FOLFIRINOX chemotherapy.

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致癌基因 GALNT5 通过激活胰腺导管腺癌中的 MYH9/ NOTCH/ DDR 轴产生 FOLFIRINOX 抗药性。
化疗耐药一直是胰腺导管腺癌(PDAC)治疗过程中面临的巨大挑战。目前治疗PDAC的一线化疗方案包括以吉西他滨为基础的方案,如AG方案(白蛋白紫杉醇和吉西他滨);以氟尿嘧啶为基础的方案,如FOLFIRINOX方案(5-氟尿嘧啶5-FU、奥沙利铂、伊立替康);以及针对BRCA基因突变患者的以铂为基础的方案。在探索吉西他滨和铂类药物耐药机制方面做了大量工作,但对 FOLFIRINOX 方案耐药机制的研究却很少。因此,我们发现多肽 N-乙酰半乳糖氨基转移酶 5(GALNT5)是 FOLFIRINOX 方案耐药的重要调节因子和潜在治疗靶点。研究人员进行了菌落形成试验和流式细胞术试验,以探讨 GALNT5 在接受 FOLFIRINOX 治疗的 PDAC 细胞增殖和凋亡中的作用。计算了 GALNT5 敲除和过表达细胞系的 IC50 变化。通过 RNA-seq 和 GSEA(基因组富集分析)来探索潜在的机制。为了验证相关通路,还进行了 WB(免疫印迹)、实时 PCR 和 IF(免疫荧光)分析。建立了小鼠正位异种移植 PDAC 模型来研究 GALNT5 在体内的功能。GALNT5 在 PDAC 组织中高表达,预示着 PDAC 的不良预后。GALNT5在PDAC细胞中的上调通过抑制DNA损伤使PDAC产生FOLFIRINOX耐药。此外,GALNT5与MYH9相互作用,从而参与NOTCH通路的激活,从而阻碍FOI诱导的DNA损伤。GALNT5促进FOLFIRINOX耐药的功能在体内得到了验证。在这项研究中,我们发现在PDAC中异常过表达的GALNT5通过与MYH9相互作用参与了NOTCH通路的激活,从而抑制了DDR以实现FOLFIRINOX耐药并导致不良预后。我们发现 GALNT5 是 FOLFIRINOX 化疗耐药的 PDAC 患者的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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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