View source for Section 3.2.7PI3K/AKT/mTOR signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)

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<b>From publication:</b> "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8<br> https://doi.org/10.1038/s41392-020-0110-5 <br><h3><u>PI3K/AKT/mTOR signaling pathway in CSCs</u></h3><p>Phosphatidylinositol-3-kinase (PI3K) is an intracellular phosphatidylinositol kinase. It consists of the regulatory subunit p85 and catalytic subunit p110, which have serine/threonine (Ser/Thr) kinase and phosphatidylinositol kinase activities. AKT is a serine/threonine kinase that is expressed as three isoforms: AKT1, AKT2, and AKT3. AKT proteins are crucial effectors of PI3K and are directly activated in response to PI3K. One of the key downstream target genes of AKT is the mammalian target of rapamycin (mTOR) complex, which is a conserved serine/threonine kinase. It forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 consists of mTOR, raptor, mLST8, and two negative regulators, PRAS40 and DEPTOR. mTORC2 phosphorylates AKT at serine residue 473, which leads to full AKT activation.</p><p>Studies show that mutations in PTEN lead to the inhibition of PI3K/mTOR signaling in glioblastoma multiforme. However, deletion of PTEN in neural stem cells leads to a neoplastic phenotype that includes cell growth promotion, resistance to cell apoptosis, and increased migratory and invasive properties in vivo. Inactivation of PTEN and activation of protein kinase B have been found in other solid tumors, such as myeloproliferative neoplasia and leukemia. Therefore, the PI3K/mTOR signaling pathway is vital for cell proliferation and survival. Abnormal activation of PI3K/mTOR signaling is found in some cancers, such as non-small-cell lung cancer, breast cancer, prostate cancer, Burkitt lymphoma, esophageal adenocarcinoma, and colorectal cancer.</p><p>Although PI3K/AKT/mTOR has been extensively studied in cancers, there are few studies in CSCs. PI3K/Akt/mTOR signaling is involved in ovarian cancer cell proliferation and the epithelial-mesenchymal transition. This signaling activation also enhances the migration and invasion of prostate and pancreatic CSCs. Downregulation of PTEN induces PI3K activation to promote survival, maintenance of stemness, and tumorigenicity of CD133+/CD44+ prostate cancer stem-like cell populations. PI3K activation promotes cell proliferation, migration, and invasion in ALDH+CD44high head and neck squamous CSCs. Activation of mTOR promotes the survival and proliferation of breast CSCs and nasopharyngeal carcinoma stem cells. mTORC1 activation also increases aldehyde dehydrogenase 1 (ALDH1) activity in colorectal CSCs. Activation of mTORC2 upregulates the expression of the hepatic CSC marker EpCAM (epithelial cellular adhesion molecule) and tumorigenicity in hepatocellular CSCs. Nucleotide-binding domain and leucine-rich repeats (NLRs) belong to a large family of cytoplasmic sensors. NLRC3 (also known as CLR16.2 or NOD3) is associated with PI3Ks and blocks activation of PI3K-dependent kinase AKT in colorectal CSCs.</p><p>In addition, some studies have shown that the mTOR signaling pathway is closely related to the metabolism of CSCs. For example, low folate (LF) stress reprograms metabolic signals through the activated mTOR signaling pathway, promoting the metastasis and tumorigenicity of lung cancer stem-like cells. However, matcha green tea (MGT), an inhibitor of mTOR, inhibits the proliferation of breast CSCs by targeting mitochondrial metabolism, glycolysis, and multiple cell signaling pathways. A link between the PI3K/Akt/mTOR pathway and CSCs is clearly evident.</p>