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Signaling by PI3K/Akt is frequently activated in cancerous mechanisms, and this activation can be accomplished via gain-of-function mutations in PI3KCA (encoding catalytic subunit p110alpha), PIK3R1 (encoding regulatory subunit p85alpha) and Akt. Loss-of-function mutations constantly activate the PI3K/ Akt pathway in tumor suppressor genes such as PTEN. Furthermore, loss-of-function mutations related to the phosphatase domain of PTEN are frequently found in sporadic cancers and PTEN hamartoma tumor syndromes (PHTS). On the other hand, inactivation of PTEN can be accomplished by gene deletion, epigenetic silencing, and overexpression of microRNAs that target PTEN mRNA. Cells with impaired PTEN function enhanced PIP3 and therefore accelerated Akt activity. Furthermore, enhanced Akt activity phosphorylates a series of substrates to control downstream cell processes, including apoptosis, protein synthesis, metabolism and cell cycle. Irregular PTEN expression is reported to occur in ∼30% of primary prostate cancer cases and ∼65% of metastatic cancer cases, while restoring PTEN expression could inhibit the PI3K/ Akt/mTOR signaling pathway, thus avoiding the growth of cancer cells.
The PI3K-Akt signaling pathway can be activated by various types of cellular stimuli or toxic insults and regulates fundamental cellular functions. Akt signaling is one of the key outcomes of receptor tyrosine kinase (RTK) activation. Mechanistically, Akt is activated by the cellular second messenger PIP3, a phospholipid generated by PI3K. In unstimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains directly or indirectly through adaptor proteins, leading to a conformational change in PI3K IA heterodimer that relieves inhibition of p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, thus converting it into PIP3, this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits Akt to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of Akt. Phosphorylation of this serine induces a conformation change in Akt, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both threonine and serine residues is required to fully activate Akt. Akt phosphorylated at both serine and threonine residues dissociates from the plasma membrane and acts as a serine/threonine kinase that phosphorylates a number of cytosolic and nuclear targets involved in the regulation of cell metabolism, survival and gene expression.
Because of their clear involvement in human cancers, PI3K and Akt are targets of considerable interest in the development of small-molecule inhibitors. Although none of the currently available inhibitors display a preference for mutant variants of PIK3CA or Akt, several inhibitors targeting the wild-type kinases are undergoing clinical trials. These include dual PI3K/mTOR inhibitors, class I PI3K inhibitors, pan-PI3K inhibitors, and pan- Akt inhibitors. While none have yet been approved for clinical use, these agents reveal promising results for future therapeutics. Trichothecene macrolides comprise a class of valuable leading compounds in developing anticancer drugs. However, there are few reports concerning their anticancer mechanisms, especially the anticancer mechanism of the 10,13-cyclotrichothecane derivatives that are found mainly in symbiotic fungi. As a trichothecene macrolides derivatives, Mytoxin B were found to reduce the activity of the PI3K/Akt signaling pathway that was similar to the effect of LY294002 (a potent and specific PI3K inhibitor), suggesting that Mytoxin B might induce human hepatocarcinoma cell line SMMC-7721 cells apoptosis via PI3K/Akt pathway.