GFPT2 expression is induced by gemcitabine administration and enhances invasion by activating the hexosamine biosynthetic pathway in pancreatic cancer.

IF 4.2 3区医学 Q2 ONCOLOGY

Clinical & Experimental Metastasis Pub Date : 2024-10-01 Epub Date: 2024-06-18 DOI:10.1007/s10585-024-10298-y

Kent Miyazaki, Kyohei Ariake, Satoko Sato, Takayuki Miura, Jingyu Xun, Daisuke Douchi, Masaharu Ishida, Hideo Ohtsuka, Masamichi Mizuma, Kei Nakagawa, Takashi Kamei, Michiaki Unno

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Abstract

Our previous studies revealed a novel link between gemcitabine (GEM) chemotherapy and elevated glutamine-fructose-6-phosphate transaminase 2 (GFPT2) expression in pancreatic cancer (PaCa) cells. GFPT2 is a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP). HBP can enhance metastatic potential by regulating epithelial-mesenchymal transition (EMT). The aim of this study was to further evaluate the effect of chemotherapy-induced GFPT2 expression on metastatic potential. GFPT2 expression was evaluated in a mouse xenograft model following GEM exposure and in clinical specimens of patients after chemotherapy using immunohistochemical analysis. The roles of GFPT2 in HBP activation, downstream pathways, and cellular functions in PaCa cells with regulated GFPT2 expression were investigated. GEM exposure increased GFPT2 expression in tumors resected from a mouse xenograft model and in patients treated with neoadjuvant chemotherapy (NAC). GFPT2 expression was correlated with post-operative liver metastasis after NAC. Its expression activated the HBP, promoting migration and invasion. Treatment with HBP inhibitors reversed these effects. Additionally, GFPT2 upregulated ZEB1 and vimentin expression and downregulated E-cadherin expression. GEM induction upregulated GFPT2 expression. Elevated GFPT2 levels promoted invasion by activating the HBP, suggesting the potential role of this mechanism in promoting chemotherapy-induced metastasis.

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胰腺癌患者服用吉西他滨会诱导 GFPT2 的表达，并通过激活己胺生物合成途径增强侵袭能力。

我们之前的研究揭示了吉西他滨（GEM）化疗与胰腺癌（PaCa）细胞中谷氨酰胺-6-磷酸果糖转氨酶 2（GFPT2）表达升高之间的新联系。GFPT2 是己胺生物合成途径（HBP）中的限速酶。HBP 可通过调节上皮-间质转化（EMT）增强转移潜力。本研究旨在进一步评估化疗诱导的 GFPT2 表达对转移潜能的影响。研究采用免疫组化分析法评估了小鼠异种移植模型中 GEM 暴露后 GFPT2 的表达情况以及化疗后患者临床标本中 GFPT2 的表达情况。研究还探讨了 GFPT2 在 HBP 激活中的作用、下游通路以及 GFPT2 表达受调控的 PaCa 细胞的细胞功能。在小鼠异种移植模型切除的肿瘤和接受新辅助化疗（NAC）的患者中，GEM暴露增加了GFPT2的表达。GFPT2 的表达与 NAC 术后肝转移相关。它的表达激活了HBP，促进了迁移和侵袭。用HBP抑制剂治疗可逆转这些效应。此外，GFPT2 上调 ZEB1 和波形蛋白的表达，下调 E-cadherin 的表达。GEM 诱导可上调 GFPT2 的表达。GFPT2水平的升高通过激活HBP促进了侵袭，这表明该机制在促进化疗诱导的转移中可能发挥作用。

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

Clinical & Experimental Metastasis 医学-肿瘤学

CiteScore

7.80

自引率

5.00%

发文量

审稿时长

12 months

期刊介绍： The Journal''s scope encompasses all aspects of metastasis research, whether laboratory-based, experimental or clinical and therapeutic. It covers such areas as molecular biology, pharmacology, tumor biology, and clinical cancer treatment (with all its subdivisions of surgery, chemotherapy and radio-therapy as well as pathology and epidemiology) insofar as these disciplines are concerned with the Journal''s core subject of metastasis formation, prevention and treatment.