The main feature of cancer cells - the ability to adapt to stressful situations, such as a shortage of nutrients. Fast-growing tumor cells have to fight the ever-decreasing supply of nutrients to survive and proliferate. Targeting these adaptive mechanisms can be an effective approach in the treatment of cancer.
Scientists from the Institute of medical discoveries Sanford Burnham recently found an alternative metabolic pathway that can be used by cancer cells to survive. According to the results of their work, published in «Molecular Cell» magazine, the two proteins of the family of enzymes PI5P4K (PI5P4Kα and PI5P4Kβ) play a key role in autophagy - a process that provides a starving the cells of nutrients. The researchers believe that targeting these proteins for violations of autophagy in cancer cells is an exciting therapeutic strategy that can help in the treatment of cancer and reduce toxicity.
Stress and Survival
Cells were deprived of nutrients, can maintain a sufficient level of energy due to the destruction or recycling of unnecessary or dysfunctional cellular components. This survival mechanism known as autophagy, plays a key role in various processes (e.g., in the development and aging of the organism). He often disrupted in diseases such as neurodegenerative disorders, myopathy of skeletal muscle, heart disease and liver cancer.
During autophagy cellular components, such as an abnormal molecule or damaged organelles sequestered in vesicles (Autophagosomes). These vesicles fuse with organelles (lysosomes), which comprise enzymes that destroy the molecule. Although strict control of autophagy is the key to survival, scientists enough is known about the signaling molecules that regulate this critical process.
In the new study, researchers found that a family of enzymes PI5P4K, whose biological functions were previously unknown to play a key role in the process of autophagy during metabolic stress. Removal of genes encoding enzymes Pip4k2a Pip4k2b and in this way, in mice caused liver cells and accumulation of lipoid autophagic vesicles during fasting. Similar changes were observed in worms that lack nutrients, who was absent PI5P4K.
Additional tests have shown that the cause of these disorders of autophagy. Starving cells lacking Pip4k2a, Pip4k2b, and the tumor suppressor p53 demonstrated that the autophagic can not fuse with lysosomes. This reduced supply of nutrients such as glutathione and amino acids, in addition to a key cellular metabolites, including Acetyl-CoA. "So we have found a way that enhances the ability to multi-cellular organisms to digest the lipids and survive periods of nutrient deprivation" - the scientists noted.
In a study published in the «Cell» magazine in 2013, the same scientists found that many types of breast cancers express high levels PI5P4Kα and PI5P4Kβ. They have also demonstrated that these enzymes play an important role in the growth of breast cancer cells with deficiency of p53. Moreover, Pip4k2a Pip4k2b deficit and sharply reduced the formation of tumors and increased the survival of mice with lack of p53. But at that time it was unclear how PI5P4K enzymes affects the growth of tumor cells.
New research has shown that these enzymes enhance the ability of cancer cells to adapt to a deficiency of nutrients, often observed in the tumor microenvironment. They found that PI5P4K inhibitors may effectively treat tumors with mutations in p53, inhibiting autophagy.