Exploring the ""Warburg Effect"" for Cancer Therapy - Targeting Lactate Transport in Cervical Cancer

Abstract

Introduction: The Warburg effect, which consists in the up-regulation of the glycolytic metabolism, even in the presence of oxygen, has been described as an important adaptive mechanism to overcome intermittent hypoxia in pre-malignant lesions. In this context, monocarboxylate transporters (MCTs) emerge as important players due to their dual function as lactate exporters and tumour intracellular pH regulators. We have recently described the up-regulation of monocarboxylate transporter 1 (MCT1) along the progression towards invasive cervical carcinoma. Therefore, we aimed to evaluate the role of MCTs in cervical cancer survival and aggressiveness. Material and Methods: The metabolic profile of the human cervical cancer cell lines SiHa, CaSki, HeLa, Sw756, C33 and HaCat was characterised by quantification of lactate production and glucose consumption as well as evaluation of the expression of different key metabolic proteins. Additionally, MCT1 activity was inhibited using the classical inhibitor alpha-cyano-4-hydroxycinnamate (CHC) and the inhibitory effects were estimated on cell biomass (Sulforhodamine B assay), cell proliferation (BrdU incorporation), induction of apoptosis (Annexin V/PI), cell migration (‘wound healing assay’) and cell invasion (matrigel invasion chamber). Statistical analysis was performed using the GraphPad statistical software. Results and Discussion: Glucose consumption and lactate production varied among cell lines, with CaSki, HeLa and HaCat being the most glycolytic cell lines and SiHa showing the lowest rates of glucose consumption and lactate production.WhenexposingcervicalcancercellstoCHC,wefoundasignificant decrease in total cell biomass, proliferation, migration and invasion, but little effect on cell death. Further MCT1 silencing studies (shMCT1) are being conducted to validate the role of MCT1 in cervical cancer. Conclusions: In this study, we characterised for the first time the effect of MCT1 inhibition in cervical cancer cells’ survival and aggressiveness. The results herein presented point at MCT1 as a promising therapeutic target for cervical cancer therapy. Acknowledgements: Part of this work was supported by the FAPESP - São Paulo Research Foundation grant ref. 2008/03232−1 and the FCT grant ref. PTDC/SAU-FCF/104347/2008, under the scope of “Programa Operacional Temático Factores de Competitividade” (COMPETE) of “Quadro Comunitário de Apoio III” and co-financed by Fundo Comunit ́ario Europeu FEDER.