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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. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating 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 CaM. 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 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. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating 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 CaM. 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. 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 glucose levels are high, insulin and therefore IGF is produced. This signaling activates the PI3K/AKT pathway which works to promote 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. The PI3K/AKT pathway has a natural inhibitor called 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. 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. 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. 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 phosphatase and tensin homologue (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 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 PIK3CA frequently have gain of function mutations in urothelial cancer. Similar to PI3Ka, PI3Kb is expressed in many different cells, and it is mainly involved in the activation of platelets and development of thrombotic diseases. Studies have shown that PI3Kb contribute to tumor proliferation as well. Specifically, it has an important role in tumorigenesis in PTEN-negative cancers. It’s reported that interfering with the gene for PI3Kb might be a therapeutic approach for high-risk bladder cancers with mutant PTEN and E-cadherin loss. Specific isoform inhibitors to PI3Kb is a potential treatment for PTEN-deficient cancers. PI3K inhibitors may overcome drug resistance and improve advanced breast cancer (ABC) outcomes. Different PI3K inhibitors exhibit different effect against various PI3K types. Class IA pan-PI3K inhibitors have been more extensively studied than isoform specific inhibitors; Pictilisib is another pan-PI3K inhibitor with greater subunitα-inhibitor activity than buparlisib. Idelalisib is the first PI3K inhibitor approved by the US Food and Drug Administration and is utilized in the treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Copanlisib is approved for relapsed follicular lymphoma in patients who have received at least two prior systemic therapies.. Duvelisib is approved for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and relapsed/refractory follicular lymphoma, both indications for patients who have received at least two prior therapies. AKT is downstream to PI3K and is inhibited by Ipatasertib. Akt is an AGC-family kinase and a central, integral signaling node of the PAM pathway. There are three Akt isozymes, Akt1, Akt2 and Akt3. Small-molecule inhibitors of Akt1 could be especially useful to target tumors with a high prevalence of Akt1 E17K activating mutations, which is observed in 4–6% of breast cancers and 1–2% of colorectal cancer. Research towards Akt inhibition has focused on inhibition of two distinct binding sites: (1) the allosteric pocket of the inactive enzyme, and (2) the ATP binding site. Allosteric Akt inhibitors, highlighted by MK-2206, have been extensively evaluated in a clinical setting; Recently, additional allosteric Akt inhibitors have been identified. ARQ-092, is a potent pan-Akt inhibitor which can inhibit tumor growth preclinically and is currently in Phase I clinical studies.

[ "Signal transduction", "Cancer", "Apoptosis", "40S ribosomal protein S6", "Oncogene Protein v-akt", "RNA 5' Terminal Oligopyrimidine Sequence", "Lipid phosphatase activity", "phosphoinositide 3 kinase akt" ]
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