All cancer cells proliferate inappropriately. P27 is a tumor-suppressor that aids the suppression of cell proliferation by blocking progression through the cell cycle. Curiously, however, tumors rarely present with a mutated or deleted p27 gene. Instead, p27 protein levels, location, or regulation is commonly disrupted in aggressive cancers, suggesting that a functional form of the protein might play some role in tumor development. Previous work in our lab identified a novel role for p27 in cancer cell metabolism. Cells lacking the p27 protein could switch from using glucose as a carbon source to the amino acid glutamine when glucose levels drop. This suggests that cancers with deregulated p27 can modulate their metabolism based on available nutrients, providing a growth advantage by increasing adaptivity. However, oxygen is required to metabolize amino acids, whereas glucose metabolism does not require oxygen, which is important because tumors often face hypoxia (lack of oxygen). We sought to determine if the p27 metabolic switch would allow cells to switch to glucose under low oxygen conditions. Cells lacking p27 were forced to use glutamine, then oxygen levels were varied to see if cells arrested or switched back to glucose. The main methods of oxygen depletion were to seal the cell culture container off from the environment to gradually reduce oxygen levels, or to use glucose oxidase to quickly reduce oxygen levels in the culture media. Effects on ATP production and cell viability were periodically analyzed, and metabolic inhibitors were used to identify metabolic pathways being utilized. Our results contribute to a better understanding of how p27 deregulation might help tumors adapt to hypoxia.

How tumors survive suffocation: The role of p27kip1 in adapting to hypoxia

2019 Spring National Meeting

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