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Published on: August 11, 2017
Targeting mitochondrial one-carbon enzyme MTHFD2 together with pemetrexed confers therapeutic advantages in lung
Juanfen Mo1, Zhenzhen Gao2, Li Zheng1
1The Key Laboratory, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China.
Abstract:
Metabolic remodeling is the fundamental molecular feature of malignant tumors. Cancer cells require sufficient energy supplies supporting their high proliferative rate. MTHFD2, a mitochondrial one-carbon metabolic enzyme, is dysregulated in several malignancies and may serve as a promising therapeutic candidate in cancer treatment. Here, our data confirmed that MTHFD2 gene and protein was upregulated in the cancerous tissues of LUAD patients and was correlated with a poor survival in LUAD. MTHFD2 was involved in lung cancer cell proliferation, migration, and apoptosis by mediating its downstream molecules, such as DNA helicases (MCM4 and MCM7), as well as ZEB1, Vimentin and SNAI1, which contributed to tumor cell growth and epithelial-to-mesenchymal transition (EMT) process. Moreover, we identified that miRNA-99a-3p appeared to be an upstream mediator directly regulating MTHFD2 and MCM4 expression. Moreover, specific inhibition of MTHFD2 functions by siRNA or a chemical compound, improved anti-tumor sensitivities induced by pemetrexed in LUAD. Taken together, our study revealed the underlying molecular mechanisms of MTHFD2 in regulating cell proliferation and identified a novel therapeutic strategy improving the treatment efficacies in LUAD.
Insights
MTHFD2, a key metabolic enzyme, is upregulated in lung adenocarcinoma (LUAD), driving cancer growth and poor survival. Inhibiting MTHFD2 enhances chemotherapy effectiveness, offering a new therapeutic strategy for LUAD patients.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Metabolic reprogramming is crucial for cancer cell proliferation.
- MTHFD2, a mitochondrial enzyme, is implicated in various cancers.
- Understanding MTHFD2's role in lung adenocarcinoma (LUAD) is vital for targeted therapies.
Purpose of the Study:
- To investigate the role of MTHFD2 in LUAD progression.
- To identify molecular mechanisms and upstream regulators of MTHFD2 in LUAD.
- To evaluate MTHFD2 inhibition as a therapeutic strategy for LUAD.
Main Methods:
- Gene and protein expression analysis in LUAD tissues.
- Assessment of MTHFD2's impact on cell proliferation, migration, and apoptosis.
- Investigation of downstream effectors including MCM4, MCM7, ZEB1, Vimentin, and SNAI1.
- Identification of miRNA-99a-3p as a regulator of MTHFD2 and MCM4.
- Evaluation of MTHFD2 inhibition using siRNA and chemical compounds in combination with pemetrexed.
Main Results:
- MTHFD2 expression is significantly upregulated in LUAD tissues and correlates with poor patient survival.
- MTHFD2 promotes LUAD cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT).
- miRNA-99a-3p directly targets and regulates MTHFD2 and MCM4 expression.
- Inhibition of MTHFD2 enhances LUAD cell sensitivity to pemetrexed chemotherapy.
Conclusions:
- MTHFD2 plays a critical role in LUAD pathogenesis by regulating cell metabolism and EMT.
- miRNA-99a-3p acts as an upstream regulator of MTHFD2 in LUAD.
- Targeting MTHFD2 presents a promising therapeutic strategy to improve LUAD treatment outcomes, particularly in combination with existing chemotherapies.
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