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. Phosphoinositide 3-kinase (PI3K) phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, and activating phosphatidylinositol 3-phosphates and mTOR, which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and calmodulin. Both leptin and insulin recruit PI3K signalling for metabolic regulation. 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.
Proliferation of neural stem cells
Response to glucose Neural stem cells (NSCs) in the brain must find a balance between maintaining their multipotency by self renewing and proliferating as opposed to differentiating and becoming quiescent. The PI3K/AKT pathway is crucial in this decision making process. NSCs are able to sense and respond to changes in the brain or throughout the organism. When blood glucose levels are elevated acutely, insulin is released from the pancreas. Activation of insulin receptors activates the PI3K/AKT pathway, which promotes proliferation. In this way, when there is high glucose and abundant energy in the organism, the PI3K/AKT pathway is activated and NSCs tend to proliferate. When there are low amounts of available energy, the PI3K/AKT pathway is less active and cells adopt a quiescent state. This occurs, in part, when AKT phosphorylates FOXO, keeping FOXO in the cytoplasm. FOXO, when dephosphorylated, can enter the nucleus and work as a transcription factor to promote the expression of various tumor suppressors such as p27 and p21. These tumor suppressors push the NSC to enter quiescence. FOXO knockouts lose the ability for cells to enter a quiescent state as well as cells losing their neural stem cell character, possibly entering a cancer like state.
PTEN The PI3K/AKT pathway has a natural inhibitor called Phosphatase and tensin homolog (PTEN) whose function is to limit proliferation in cells, helping to prevent cancer. Knocking out PTEN has been shown to increase the mass of the brain because of the unregulated proliferation that occurs. PTEN works by dephosphorylating PIP3 to PIP2 which limits AKTs ability to bind to the membrane, decreasing its activity. PTEN deficiencies can be compensated downstream to rescue differentiation or quiescence. Knocking out PTEN is not as serious as knocking out FOXO for this reason.
CREB The cAMP response element CREB is closely related to the cell decision to proliferate or not. Cells that are forced to overexpress AKT increase the amount of CREB and proliferation compared to wild type cells. These cells also express less glial and neural cell markers such as GFAP or β-tubulin. This is because CREB is a transcription factor that influences the transcription of cyclin A which promotes proliferation. For example, adult hippocampal neural progenitor cells need abeyance as stem cells to differentiate later. This is regulated by Shh. Shh works through a slow protein synthesis dependence, which stimulates other cascades that work synergistically with the PI3K/AKT pathway to induce proliferation. Then, the other pathway can be turned off and the effects of the PI3K/AKT pathway become insufficient in stopping differentiation. The specifics of this pathway are unknown.
Roles in cancer
Ovarian cancer PI3K/ AKT/mTOR pathway is a central regulator of ovarian cancer. PIM kinases are over expressed in many types of cancers and they also contribute to the regulation of ovarian cancer. PIM are directly and indirectly found to activate mTOR and its upstream effectors like AKT. Besides, PIM kinases can cause phosphorylation of IRS, which can alter PI3K. This indicates the close interaction of PIM with PI3K/ AKT/mTOR cascade and its components. Similarly, AKT has also been reported to perform the BAD phosphorylation in OC cells. PIM and the PI3K/AKT/mTOR network both can inhibit the P21 and P27 expressions in OC cells. These data suggest a strong possibility of interaction and relevance of PIM kinases and the PI3K/AKT/mTOR network in the regulation of ovarian cancer. However, targeting this pathway in ovarian cancer has been challenging with several trials failing to achieve sufficient clinical benefit.
Breast cancer In many kinds of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are the most common genomic abnormalities. The most common known aberrations include the PIK3CA gene mutation and the loss-of-function mutations or epigenetic silencing of PTEN. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway is activated in approximately 30–40% of BC cases. In triple-negative breast cancer (TNBC), oncogenic activation of the PI3K/AKT/mTOR pathway can happen as a function of overexpression of upstream regulators like EGFR, activating mutations of PIK3CA, loss of function or expression of phosphatase and tensin homolog (PTEN), and the proline-rich inositol polyphosphatase, which are downregulators of PI3K. It is consistent with the hypothesis that PI3K inhibitors can overcome resistance to endocrine therapy when it is acquired
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