Abstract
Metabolic reprogramming is considered one of the hallmarks in cancer and is characterized by increased glycolysis and lactate production, even in the presence of oxygen, which leads the cancer cells to a process called “aerobic glycolysis” or “Warburg effect”. The E6 and E7 oncoproteins of human papillomavirus 16 (HPV 16) favor the Warburg effect through their interaction with a molecule that regulates cellular metabolism, such as p53, retinoblastoma protein (pRb), c-Myc, and hypoxia inducible factor 1α (HIF-1α). Besides, the impact of the E6 and E7 variants of HPV 16 on metabolic reprogramming through proteins such as HIF-1α may be related to their oncogenicity by favoring cellular metabolism modifications to satisfy the energy demands necessary for viral persistence and cancer development. This review will discuss the role of HPV 16 E6 and E7 variants in metabolic reprogramming and their contribution to developing and preserving the malignant phenotype of cancers associated with HPV 16 infection.
Highlights
Active HIF1 promotes the expression of glucose transporters such as GLUT1 that increases the amount of glucose in the cytoplasm [32,33], oncogenes such as c-Myc, and glycolytic enzymes related to the Warburg effect such as hexokinase 2 (HK2), PFKFB or PFK-2, ALDOA- B, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), PGK1, ENO1, pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA)-B
16 of the AA, E, and Afr2a sublineages can alter glucose metabolism by inducing p53 degradation, leading to increased expression of enzymes, transporters, and receptors involved in glycolysis such as GLUT1, GLUT4, insulin receptor (INSR), HK2, TP53 induced glycolysis regulatory phosphatase (TIGAR), phosphofructokinase 1 (PFK1), PKM2, MCT1, pyruvate carboxylase (PC) (Figure 1), and the positive regulation of the transcription factors hypoxia inducible factor 1α (HIF-1α) and c-Myc related to the transcription of genes involved in the glycolysis
The Wnt/βcatenin pathway regulates the activation of the tyrosine kinase receptors that leads to the activation of the PI3K/AKT pathway, which leads to an increase in glucose metabolism, which in turn leads to the activation of the Warburg effect through HIF-1α, which in turn increases the expression of GLUT, HK, PKM2, lactate dehydrogenase A (LDH-A), and pyruvate dehydrogenase kinase (PDK), resulting in increased cytosolic pyruvate, of which most is converted to lactate and released to the extracellular environment, while a small part is converted to acetyl-CoA, which enters the tricarboxylic acids (TCA) cycle and is converted to citrate to promote lipid and protein synthesis [136]
Summary
16 variants alter the expression of various genes related to apoptosis, adhesion, metastasis, angiogenesis, and metabolism [12]. These variants interact with multiple cellular proteins such as p53, retinoblastoma protein (pRb), p300/CBP, and pyruvate kinase 2 (PKM2), promoting gain or loss of their functions [13]. These have been associated with a more significant oncogenic potential of these variants and the severity of precancerous lesions [14,15]. This review addresses the oncogenic role of HPV 16 variants in metabolic reprogramming modulation as a possible mechanism involved in carcinogenesis
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