FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression.

Abstract

PURPOSE:

The transcription factor Forkhead box protein M1 (FOXM1) plays critical roles in cancer development and progression. However, the regulatory role and underlying mechanisms of FOXM1 in cancer metabolism are unknown. In this study, we characterized the regulation of aerobic glycolysis by FOXM1 and its impact on pancreatic cancer metabolism.

EXPERIMENTAL DESIGN:

The effect of altered expression of FOXM1 on expression of glycolytic enzymes and tumor development and progression was examined using animal models of pancreatic cancer. Also, the underlying mechanisms of altered pancreatic cancer glycolysis were analyzed using in vitro molecular biology. The clinical relevance of aberrant metabolism caused by dysregulated FOXM1 signaling was determined using pancreatic tumor and normal pancreatic tissue specimens.

RESULTS:

We found that FOXM1 did not markedly change the expression of most glycolytic enzymes except for phosphoglycerate kinase 1 (PGK-1) and lactate dehydrogenase A (LDHA). FOXM1 and LDHA were overexpressed concomitantly in pancreatic tumors and cancer cell lines. Increased expression of FOXM1 upregulated the expression of LDHA at both the mRNA and protein level and elevated LDH activity, lactate production, and glucose utilization, whereas reduced expression of FOXM1 did the opposite. Further studies demonstrated that FOXM1 bound directly to the LDHA promoter region and regulated the expression of the LDHA gene at the transcriptional level. Also, elevated FOXM1-LDHA signaling increased the pancreatic cancer cell growth and metastasis.

CONCLUSIONS:

Dysregulated expression and activation of FOXM1 play important roles in aerobic glycolysis and tumorigenesis in patients with pancreatic cancer via transcriptional regulation of LDHA expression.

• Authors: Jiujie Cui, Min Shi, Dacheng Xie, Daoyan Wei, Zhiliang Jia, Shaojiang Zheng, Yong Gao, Suyun Huang, Keping Xie
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 10 Pg. 2595-606 (May 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24634381 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• FOXM1 protein, human
• Forkhead Box Protein M1
• Forkhead Transcription Factors
• Isoenzymes
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5

Topics

• Animals
• Cell Line, Tumor
• Disease Progression
• Forkhead Box Protein M1
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Glycolysis (genetics)
• Humans
• Immunohistochemistry
• Isoenzymes (genetics, metabolism)
• L-Lactate Dehydrogenase (genetics, metabolism)
• Lactate Dehydrogenase 5
• Mice, Nude
• Neoplasm Metastasis
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Promoter Regions, Genetic (genetics)
• Protein Binding
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Tissue Array Analysis
• Transcriptional Activation
• Transplantation, Heterologous