Nicole Prescott

Introduction. Despite countless new discoveries and therapeutic advances, cancer continues to thwart our understanding of its progression and claims over half a million deaths per year.¹  Metabolic reprogramming is critical to cancer’s lethality. In the 1920s, Otto Warburg postulated that tumor metabolism is characterized by the production of lactate in a normoxic environment.¹  Recent data implicates a Lactate/HIF-1a/VEGF metabolic axis that contributes to cancer immunity.²  Overexpression of mutant HIF-1a conferred resistance therapy induced cell cycle arrest.³  In contrast, silencing the expression of HIF-1a attenuated the Warburg Effect, inhibiting progression and invasion of certain cell lines.⁴  These factors are also implicated in radiation resistance of cancer cells and exploring this mechanism further could lead to targeted therapies that enhance radiation therapy in the treatment of human cancer.⁵  Methods. Head and neck squamous cell carcinoma cells were treated with Cetuximab and knockdown of HIF-1a expression by siRNA was conducted and detected by Western blotting.²  Human pancreatic cancer cell line (BxPC-3) were transfected with siRNA, followed by RT-PCR and Western blot analysis to detect HIF-1a expression.⁴  Lactate content was assessed in cells after exposure to both normoxic and hypoxic conditions.⁴  Growth inhibition rates of HeLa cells were detected by tetrazolium- based colorimetric cellular assay (MTT) and flow cytometry (FCM), and expression of HIF-1a and VEGF were observed by Western blot and reverse transcription polymerase chain reaction (RT-PCR).⁵  Results.  HIF-1a knockdown delays cancer cell growth, thwarts invasiveness, and increases apoptosis in hypoxic conditions.⁴  Cetuximab inhibits aerobic glycolysis and drug resistance is linked to increased glycolytic flux.²  Consumption of glucose and production of lactate were reduced in a HIF-1a downregulation-dependent manner by Cetuximab.²  Hypoxic conditions enhanced the radiation resistance dependent on HIF-1α by elevating the expression of VEGF.⁵  Conclusions.  Lactate, HIF-1a, and VEGF proteins have been shown to contribute to the metabolic shift that is associated with the progression of a malignant phenotype.  In the future, we might inhibit cancer progression and radiation resistance by targeting these proteins.⁵  However, in order to truly bridge the gap between research and the patient bedside, it is critical that we study further tumor cell metabolism in the context of their local environment.

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