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Tumor promoting effect of PDLIM2 downregulation involves mitochondrial ROS, oncometabolite accumulations and HIF-1α
Jing-Xing Yang1, Yu-Chen Chuang1, Jen-Chih Tseng1
1Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan.
Background:
Cancer is characterized by dysregulated cellular metabolism. Thus, understanding the mechanisms underlying these metabolic alterations is important for developing targeted therapies. In this study, we investigated the pro-tumoral effect of PDZ and LIM domain 2 (PDLIM2) downregulation in lung cancer growth and its association with the accumulation of mitochondrial ROS, oncometabolites and the activation of hypoxia-inducible factor-1 (HIF-1) α in the process.
Methods:
Databases and human cancer tissue samples were analyzed to investigate the roles of PDLIM2 and HIF-1α in cancer growth. DNA microarray and gene ontology enrichment analyses were performed to determine the cellular functions of PDLIM2. Seahorse assay, flow cytometric analysis, and confocal microscopic analysis were employed to study mitochondrial functions. Oncometabolites were analyzed using liquid chromatography-mass spectrometry (LC-MS). A Lewis lung carcinoma (LLC) mouse model was established to assess the in vivo function of PDLIM2 and HIF-1α.
Results:
The expression of PDLIM2 was downregulated in lung cancer, and this downregulation correlated with poor prognosis in patients. PDLIM2 highly regulated genes associated with mitochondrial functions. Mechanistically, PDLIM2 downregulation resulted in NF-κB activation, impaired expression of tricarboxylic acid (TCA) cycle genes particularly the succinate dehydrogenase (SDH) genes, and mitochondrial dysfunction. This disturbance contributed to the accumulation of succinate and other oncometabolites, as well as the buildup of mitochondrial reactive oxygen species (mtROS), leading to the activation of hypoxia-inducible factor 1α (HIF-1α). Furthermore, the expression of HIF-1α was increased in all stages of lung cancer. The expression of PDLIM2 and HIF-1α was reversely correlated in lung cancer patients. In the animal study, the orally administered HIF-1α inhibitor, PX-478, significantly reduces PDLIM2 knockdown-promoted tumor growth.
Conclusion:
These findings shed light on the complex action of PDLIM2 on mitochondria and HIF-1α activities in lung cancer, emphasizing the role of HIF-1α in the tumor-promoting effect of PDLIM2 downregulation. Additionally, they provide new insights into a strategy for precise targeted treatment by suggesting that HIF-1α inhibitors may serve as therapy for lung cancer patients with PDLIM2 downregulation.
Insights
PDZ and LIM domain 2 (PDLIM2) downregulation promotes lung cancer by impairing mitochondrial function and activating hypoxia-inducible factor-1α (HIF-1α). HIF-1α inhibitors show promise for treating lung cancer with low PDLIM2 expression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Lung cancer exhibits altered cellular metabolism, necessitating research into metabolic dysregulation mechanisms for targeted therapies.
- PDZ and LIM domain 2 (PDLIM2) downregulation is investigated for its pro-tumoral effects in lung cancer.
- The study explores the link between PDLIM2 downregulation, mitochondrial reactive oxygen species (ROS), oncometabolites, and hypoxia-inducible factor-1α (HIF-1α) activation.
Purpose of the Study:
- To investigate the pro-tumoral role of PDLIM2 downregulation in lung cancer.
- To elucidate the association between PDLIM2, mitochondrial dysfunction, oncometabolite accumulation, and HIF-1α activation.
- To evaluate the therapeutic potential of targeting HIF-1α in lung cancer with PDLIM2 downregulation.
Main Methods:
- Analysis of human lung cancer tissues and databases to assess PDLIM2 and HIF-1α roles.
- DNA microarray and gene ontology analysis to determine PDLIM2 functions.
- Seahorse assays, flow cytometry, and confocal microscopy for mitochondrial function studies.
- Liquid chromatography-mass spectrometry (LC-MS) for oncometabolite analysis.
- Establishment of a Lewis lung carcinoma (LLC) mouse model for in vivo validation.
Main Results:
- PDLIM2 expression is decreased in lung cancer, correlating with poor patient prognosis.
- PDLIM2 downregulation leads to NF-κB activation, impaired tricarboxylic acid (TCA) cycle gene expression (e.g., succinate dehydrogenase), and mitochondrial dysfunction.
- This dysfunction causes succinate accumulation, increased mitochondrial ROS (mtROS), and subsequent HIF-1α activation.
- HIF-1α expression is elevated in all lung cancer stages and inversely correlated with PDLIM2 expression.
- In vivo, the HIF-1α inhibitor PX-478 significantly suppressed tumor growth in a PDLIM2 knockdown model.
Conclusions:
- PDLIM2 influences mitochondrial function and HIF-1α activity in lung cancer.
- HIF-1α plays a crucial role in the tumor-promoting effects of PDLIM2 downregulation.
- HIF-1α inhibitors represent a potential targeted therapy for lung cancer patients with PDLIM2 downregulation.
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