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

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

Clin Cancer Res

Authors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Published: May 2014

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024335PMC
http://dx.doi.org/10.1158/1078-0432.CCR-13-2407DOI Listing

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