The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways are both necessary for cell growth and survival, in physiological as well as in pathological conditions. They are interconnected in a unique pathway which is referred to as the PI3K/AKT/mTor signal pathway.
The mammalian target of rapamycin (mTOR) is a protein serine/threonine kinase that was initially identified as the cellular target of rapamycin. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. The kinase is activated in response to hormones, growth factors and some nutrients. Data from preclinical studies have indicated that factors that antagonize the mTOR pathway may exert an antitumor effect on lung cancer.
The Akt Pathway, or PI3K-Akt Pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are phosphatidylinositol 3-kinase (PI3K) and Akt, or Protein Kinase B. The pathway is highly regulated by multiple mechanisms, often involving cross-talk with other signalling pathways. Problems with PI3K-Akt pathway regulation can lead to increase in signalling activity. This has been linked to a range of diseases such as cancer and type II diabetes. A major antagonist of PI3K activity is PTEN, a tumour suppressor which is often mutated or lost in cancer cells. Akt phosphorylates as many as 100 different substrates, leading to a wide range of effects on the cell.
There are many known factors that enhance the PI3K/AKT pathway including EGF, IGF-1, and insulin. The pathway is antagonized by various factors including PTEN, GSK3B, and HB9. In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation. This pathway is necessary, however, to promote growth and proliferation over differentiation of adult stem cells, neural stem cells specifically. It is the difficulty in finding an appropriate amount of proliferation versus differentiation that researchers are trying to determine in order to utilize this balance in the development of various therapies. Additionally, this pathway has been found to be a necessary component in neural long term potentiation.
The PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. Over the last decade research have show that the mTOR pathway is activated during various cellular processes such as: tumor formation and angiogenesis, insulin resistance, adipogenesis and T-lymphocyte activation. mTOR is deregulated in human diseases such as cancer and type 2 diabetes.
Recent progress in that revealed PI3K/AKT/mTOR alterations and their roles in tumorigenesis has produced the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, target inhibition of PI3K/AKT/mTOR. Many others are currently in preclinical development as well as being tested in early clinical trials for many different types of cancer.
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