Abstract
BackgroundTumor metabolism is a crucial factor for the carcinogenesis of oral squamous cell carcinoma (OSCC).MethodsExpression of IGF-R1, glycolysis-related proteins (GLUT-1, HK 2, PFK-1, LDHA, TKTL1), mitochondrial enzymes (SDHA, SDHB, ATP synthase) were analyzed in normal oral mucosa (n = 5), oral precursor lesions (simple hyperplasia, n = 11; squamous intraepithelial neoplasia, SIN I-III, n = 35), and OSCC specimen (n = 42) by immunohistochemistry and real-time polymerase chain reaction (qPCR) analysis in OSCC cell lines. Metabolism-related proteins were correlated with proliferation activity (Ki-67) and apoptotic properties (TUNEL assay) in OSCC. Specificity of antibodies was confirmed by western blotting in cancer cell lines.ResultsExpression of IGF-R1, glycolysis-related proteins (GLUT-1, HK 2, LDHA, TKTL1), and mitochondrial enzymes (SDHA, SDHB, ATP synthase) were significantly increased in the carcinogenesis of OSCC. Metabolic active regions of OSCC were strongly correlated with proliferating cancer (Ki-67+) cells without detection of apoptosis (TUNEL assay).ConclusionsThis study provides the first evidence of the expression of IGF-R1, glycolysis-related proteins GLUT-1, HK 2, PFK-1, LDHA, and TKTL1, as well as mitochondrial enzymes SDHA, SDHB, and ATP synthase in the multi-step carcinogenesis of OSCC. Both, hypoxia-related glucose metabolism and mitochondrial oxidative phosphorylation characteristics are associated with the carcinogenesis of OSCC. Acidosis and OXPHOS may drive a metabolic shift towards the pentose phosphate pathway (PPP). Therefore, inhibition of the PPP, glycolysis, and targeted anti-mitochondrial therapies (ROS generation) by natural compounds or synthetic vitamin derivatives may act as sensitizer for apoptosis in cancer cells mediated by adjuvant therapies in OSCC.
Highlights
Cancer is regarded as an acquired genetic disease
Expression of Insulin-like growth factor (IGF)-R1β, glycolysis-related proteins glucose transporter 1 (GLUT-1), Hexokinase 2 (HK 2), PFK-1, Lactate dehydrogenase A (LDHA), TKTL1, mitochondrial enzymes SDHA, SDHB, and adenosine triphosphate (ATP) synthase in normal mucosa, oral precursor lesions and oral squamous cell carcinoma (OSCC) Invasive OSCC of immunohistochemical stained serial sections was confirmed by H&E staining (Additional file 1: Figure S1)
Significant correlation of proliferating cancer cells was observed with GLUT-1, TKTL1 mitochondrial markers SDHA, SDHB, and ATP synthase: GLUT-1, TKTL1, SDHA, SDHB, and ATP synthase
Summary
Cancer is regarded as an acquired genetic disease. The genetic model of multistep carcinogenesis describes the rise of malignant tumors from a single transformed cell (monoclonal theory of carcinogenesis) and subsequent development through morphologically and clinically detectable precancerous stages [1]. Tumor metabolism [5] with a special focus on increased hypoxia/glycolytic activity is regarded as a crucial factor for the carcinogenesis of OSCC and is associated with radio- and, chemotherapy resistance, as well as tumor recurrence [6,7,8,9]. Glycolysis is a major characteristic of tumor cell metabolism this pathway alone cannot account for energy usage in all types of cancer cells. The dominant metabolic process can be either glycolysis or mitochondrial oxidative metabolism based on the tumor type [15]. Both metabolic phenotypes have been associated with subsequent nutritional consequences [16,17,18,19]. Tumor metabolism is a crucial factor for the carcinogenesis of oral squamous cell carcinoma (OSCC)
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