J Exp Clin Cancer Res|胡三元主任指明结直肠癌5-FU耐药性的新机制

2022年8月3日 0条评论 364次阅读 0人点赞

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迄今为止，5-氟尿嘧啶（5-FU）的获得性耐药仍是结直肠癌（CRC）临床治疗面临的挑战，而开发目标药物以降低耐药性的努力尚未取得成功。据报道，代谢重编程是一个关键的癌症标志，并赋予包括化疗抗性在内的几种肿瘤表型。CRC中5-FU耐药的葡萄糖代谢重编程事件尚未被评估，且异常的葡萄糖代谢是否会导致CRC对5-FU产生抗性也不清楚。

2022年1月8日，山东千佛山医院普外科胡三元主任在Journal of Experimental and Clinical Cancer Research上发表了题为“ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer”的研究论文。本文对耐5-FU的CRC糖代谢异常进行了详细描述，指出CRC中增强的糖酵解和磷酸戊糖途径与HIF-1α表达增加有关。团队认为，HIF-1α是5-FU耐药CRC的潜在生物标志物，靶向HIF-1α联合5-FU可能是治疗5-FU耐药性CRC的有效治疗策略。

在本研究中，体外研究，团队建立了三个获得性5-FU抗性CRC细胞系模型，之后，测定葡萄糖和乳酸利用率，葡萄糖代谢相关酶RNA和蛋白表达，以及葡萄糖代谢产物库中间代谢物的变化，以评估葡萄糖代谢；并采用慢病毒系统建立稳定HIF1A基因敲除细胞模型。临床上，采用免疫组化和免疫荧光法检测CRC患者原发肿瘤和循环肿瘤细胞中HIF-1α的蛋白水平。最后，在体内和体外模型中评估了HIF1A基因敲低和药理学抑制对CRC中5-FU抗性的影响。

结果发现，HIF-1α诱导的葡萄糖代谢重编程赋予了CRC的5-FU抗性。HIF-1α在5-FU抗性的CRC细胞系和临床标本中表现出高表达，并且HIF-1α水平升高与CRC患者基于氟尿嘧啶类似物的化疗失败和生存率低有关。机制上，HIF-1α在5-FU耐药CRC中的上调是通过激活活性氧（ROS）介导的PI3K/Akt信号通路，以及细胞核中β-连环蛋白的异常激活的非氧依赖性机制实现的。最后，HIF-1α基因敲除和药理抑制均恢复了CRC对5-FU的敏感性。

《J Exp Clin Cancer Res|胡三元主任指明结直肠癌5-FU耐药性的新机制》

图 HIF-1α诱导葡萄糖代谢重编程在CRC中赋予5-FU耐药性的示意图。

期刊及DOI号

J Exp Clin Cancer Res. 2022 Jan 8.

doi: 10.1186/s13046-021-02229-6.

题目

ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer

摘要

背景：Acquired resistance of 5-fluorouracil (5-FU) remains a clinical challenge in colorectal cancer (CRC), and efforts to develop targeted agents to reduce resistance have not yielded success. Metabolic reprogramming is a key cancer hallmark and confers several tumor phenotypes including chemoresistance. Glucose metabolic reprogramming events of 5-FU resistance in CRC has not been evaluated, and whether abnormal glucose metabolism could impart 5-FU resistance in CRC is also poorly defined.

方法：Three separate acquired 5-FU resistance CRC cell line models were generated, and glucose metabolism was assessed by measuring glucose and lactate utilization, RNA and protein expressions of glucose metabolism-related enzymes and changes of intermediate metabolites of glucose metabolite pool. The protein levels of hypoxia inducible factor 1α (HIF-1α) in primary tumors and circulating tumor cells of CRC patients were detected by immunohistochemistry and immunofluorescence. Stable HIF1A knockdown in cell models was established with a lentiviral system. The influence of both HIF1A gene knockdown and pharmacological inhibition on 5-FU resistance in CRC was evaluated in cell models in vivo and in vitro.

结果：The abnormality of glucose metabolism in 5-FU-resistant CRC were described in detail. The enhanced glycolysis and pentose phosphate pathway in CRC were associated with increased HIF-1α expression. HIF-1α-induced glucose metabolic reprogramming imparted 5-FU resistance in CRC. HIF-1α showed enhanced expression in 5-FU-resistant CRC cell lines and clinical specimens, and increased HIF-1α levels were associated with failure of fluorouracil analog-based chemotherapy in CRC patients and poor survival. Upregulation of HIF-1α in 5-FU-resistant CRC occurred through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling and aberrant activation of β-catenin in the nucleus. Both HIF-1α gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU.

结论：HIF-1α is a potential biomarker for 5-FU-resistant CRC, and targeting HIF-1a in combination with 5-FU may represent an effective therapeutic strategy in 5-FU-resistant CRC.

关键词：HIF-1α, Metabolic reprogramming, Glycolysis, Reactive oxygen species, β-Catenin, Prognostic biomarker, 5-fluorouracil, Chemoresistance, Colorectal.