Pharmacological targeting of MTHFD2 suppresses NSCLC via the regulation of ILK signaling pathway

Feng Zhou; Ziyi Yuan; Yuyan Gong; Luyao Li; Yanmao Wang; Xian Wang; Chunbo Ma; Lehe Yang; Zhiguo Liu; Liangxing Wang; Haiyang Zhao; Chengguang Zhao; Xiaoying Huang

doi:10.1016/j.biopha.2023.114412

Pharmacological targeting of MTHFD2 suppresses NSCLC via the regulation of ILK signaling pathway

Biomed Pharmacother. 2023 May:161:114412. doi: 10.1016/j.biopha.2023.114412. Epub 2023 Feb 22.

Authors

Feng Zhou¹, Ziyi Yuan¹, Yuyan Gong¹, Luyao Li², Yanmao Wang¹, Xian Wang¹, Chunbo Ma¹, Lehe Yang², Zhiguo Liu¹, Liangxing Wang², Haiyang Zhao³, Chengguang Zhao⁴, Xiaoying Huang⁵

Affiliations

¹ Division of Pulmonary Medicine, the First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou, Key Laboratory of Heart and Lung, Zhejiang 325000, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
² Division of Pulmonary Medicine, the First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou, Key Laboratory of Heart and Lung, Zhejiang 325000, China.
³ Institute of Life Sciences, Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, Zhejiang, China. Electronic address: 20160106@wzu.edu.cn.
⁴ Division of Pulmonary Medicine, the First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou, Key Laboratory of Heart and Lung, Zhejiang 325000, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: zhaochengguang@wmu.edu.cn.
⁵ Division of Pulmonary Medicine, the First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou, Key Laboratory of Heart and Lung, Zhejiang 325000, China. Electronic address: huangxiaoying@wzhospital.cn.

PMID: 36827714
DOI: 10.1016/j.biopha.2023.114412

Abstract

Lung cancer is the most common cause of cancer related deaths worldwide with the highest mortality rate. Non-small cell lung cancer (NSCLC) accounts for about 85 % of lung cancers. Mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme and is the most differentially expressed metabolic enzyme in various tumors including lung cancer. However, little is known about how MTHFD2 functions in NSCLC. Integrin-linked kinase (ILK) signaling plays key a role in tumor progression including metastasis, proliferation and migration. Here, we show that MTHFD2 inhibition results in suppression of cell growth, migration, invasion and epithelial-mesenchymal transition (EMT) in NSCLC. Microarray analysis suggests that MTHFD2 is positively associated with ILK signaling based on western blotting results. In addition, the phosphorylation of AMPKα plays an essential role in MTHFD2 regulation of ILK signaling. Further, the small-molecule compound C18 inhibits MTHFD2 with great efficiency. C18 blocks MTHFD2/ILK signaling pathway and restrains cell growth, migration, invasion, and EMT of NSCLC and induces apoptosis. In brief, our study found that the positive impact of MTHFD2 is mediated via ILK signaling pathway in NSCLC. Thus, blocking MTHFD2 represents a promising therapeutic strategy against NSCLC clinically.

Keywords: AMPK; ILK; Inhibitor; MTHFD2; Non-small-cell lung Cancer.

MeSH terms

Carcinoma, Non-Small-Cell Lung* / drug therapy
Cell Line, Tumor
Cell Movement
Cell Proliferation
Epithelial-Mesenchymal Transition
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms* / drug therapy
Signal Transduction

Substances

integrin-linked kinase