MTHFD1 Regulates Autophagy to Promote Growth and Metastasis in Colorectal Cancer via the PI3K-AKT–mTOR Signaling Pathway

IF 2.9 2区医学 Q2 ONCOLOGY Cancer Medicine Pub Date : 2024-11-21 DOI:10.1002/cam4.70267

Zhihao Li, Haoxian Ke, Jiawei Cai, Shubiao Ye, Junfeng Huang, Chi Zhang, Ming Yuan, Ping Lan, Xianrui Wu

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Abstract

Objectives

Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) is the enzyme with the activities of methylenetetrahydrofolate dehydrogenase, methylenetetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetase. Our aim was to elucidate the function of MTHFD1 in colorectal cancer (CRC).

Methods

In vitro assessments of the proliferation, invasion, and migration abilities of CRC cells were conducted using Immunohistochemistry, Transwell invasion assays, Western blot (WB), and Cell counting Kit-8 assays. WB was also utilized to measure autophagy protein levels and PI3K-AKT-mTOR signaling pathway expression. Furthermore, the role of MTHFD1 was evaluated in vivo by using subcutaneous xenograft tumor models and lateral tail vein metastasis models of human CRC in nude mice.

Results

Overexpression of MTHFD1 promoted the abilities of tumorigenesis and metastasis in CRC in vitro and in vivo and reduced autophagy, attributing to the PI3K-AKT-mTOR signaling pathway in CRC cells. In contrast, the down-regulation of MTHFD1 increased autophagy and suppressed their proliferation, migration, and invasion.

Conclusions

MTHFD1 can modulate the PI3K-AKT-mTOR signaling pathway to suppress autophagy and stimulate tumorigenesis and metastasis.

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MTHFD1通过PI3K-AKT-mTOR信号通路调控自噬，促进结直肠癌的生长和转移

研究目的亚甲基四氢叶酸脱氢酶1（MTHFD1）是一种具有亚甲基四氢叶酸脱氢酶、亚甲基四氢叶酸环醇酶和甲酰四氢叶酸合成酶活性的酶。我们的目的是阐明 MTHFD1 在结直肠癌（CRC）中的功能：方法：使用免疫组化、Transwell 侵袭试验、Western 印迹（WB）和细胞计数试剂盒-8 试验对 CRC 细胞的增殖、侵袭和迁移能力进行体外评估。还利用WB检测了自噬蛋白水平和PI3K-AKT-mTOR信号通路的表达。此外，还利用裸鼠皮下异种移植肿瘤模型和侧尾静脉转移模型评估了 MTHFD1 在体内的作用：结果：MTHFD1的过表达促进了体外和体内CRC的肿瘤发生和转移能力，并降低了自噬，这归因于CRC细胞中的PI3K-AKT-mTOR信号通路。相反，下调MTHFD1可增加自噬，抑制其增殖、迁移和侵袭：结论：MTHFD1能调节PI3K-AKT-mTOR信号通路，抑制自噬，刺激肿瘤发生和转移。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.