Abstract
Oncogenic stress-induced senescence (OIS) prevents the ability of oncogenic signals to induce tumorigenesis. It is now largely admitted that the mitogenic effect of oncogenes requires metabolic adaptations to respond to new energetic and bio constituent needs. Yet, whether glucose metabolism affects OIS response is largely unknown. This is largely because of the fact that most of the OIS cellular models are cultivated in glucose excess. In this study, we used human epithelial cells, cultivated without glucose excess, to study alteration and functional role of glucose metabolism during OIS. We report a slowdown of glucose uptake and metabolism during OIS. Increasing glucose metabolism by expressing hexokinase2 (HK2), which converts glucose to glucose-6-phosphate (G6P), favors escape from OIS. Inversely, expressing a G6P, pharmacological inhibition of HK2, or adding nonmetabolizable glucose induced a premature senescence. Manipulations of various metabolites covering G6P downstream pathways (hexosamine, glycolysis, and pentose phosphate pathways) suggest an unexpected role of the hexosamine pathway in controlling OIS. Altogether, our results show that decreased glucose metabolism occurs during and participates to OIS.
Highlights
Otto Warburg was the first to describe a metabolic switch occurring in cancer tissues
To study glucose metabolism during oncogeneinduced senescence (OIS), we focused on human epithelial cells cultivated without glucose excess
MEK activation blocked cell growth (Figure 1b), induced the appearance of senescence-associated b-galactosidase activity (SA-b-Gal) (Figure 1c), and increased expression of a set of senescence markers: Sprouty homolog 2 (SPRY2),[21] the interleukin-8 (IL-8),[22] and the Deleted In Esophageal Cancer 1 (DEC1)[23] (Figure 1d)
Summary
Otto Warburg was the first to describe a metabolic switch occurring in cancer tissues. Cancer cells divide rapidly and need favorable energy production rates In these cells, glucose is rendered more bioavailable and metabolizable through upregulation of glucose transporters and metabolic enzymes. Glucose is rendered more bioavailable and metabolizable through upregulation of glucose transporters and metabolic enzymes Tumor imaging exploits this fact to detect the presence of tumors throughout the body: cancer cells are labeled with the glucose analog 18fluorine-fluorodeoxyglucose. Oncogenes products such as MYC, NF-kB, AKT, HIF, and E2F, and the tumor-suppressor genes products such as p53 and PTEN, which are respectively activated or inhibited in cancer, can act on either glucose transporters, glycolytic enzymes, or both, and this suggests that in cancer cells, the regulation of growth is coupled with that of metabolism.[1,2,3,4,5,6,7,8]. We used human epithelial cells cultivated at 8 mM
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