Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

Abstract

PhosphoInositide-3 Kinase (PI3K) represents a family of different classes of kinases which control multiple biological processes in mammalian cells, such as cell growth, proliferation, and survival. Class IA PI3Ks, the main regulators of proliferative signals, consists of a catalytic subunit (α, β, δ) that binds p85 regulatory subunit and mediates activation of AKT and mammalian Target Of Rapamycin (mTOR) pathways and regulation of downstream effectors. Dysregulation of PI3K/AKT/mTOR pathway in skin contributes to several pathological conditions characterized by uncontrolled proliferation, including skin cancers, psoriasis, and atopic dermatitis (AD). Among cutaneous cancers, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) display PI3K/AKT/mTOR signaling hyperactivation, implicated in hyperproliferation, and tumorigenesis, as well as in resistance to apoptosis. Upregulation of mTOR signaling proteins has also been reported in psoriasis, in association with enhanced proliferation, defective keratinocyte differentiation, senescence-like growth arrest, and resistance to apoptosis, accounting for major parts of the overall disease phenotypes. On the contrary, PI3K/AKT/mTOR role in AD is less characterized, even though recent evidence demonstrates the relevant function for mTOR pathway in the regulation of epidermal barrier formation and stratification. In this review, we provide the most recent updates on the role and function of PI3K/AKT/mTOR molecular axis in the pathogenesis of different hyperproliferative skin disorders, and highlights on the current status of preclinical and clinical studies on PI3K-targeted therapies.

SLURP-1 Controls Growth and Migration of Lung Adenocarcinoma Cells, Forming a Complex With α7-nAChR and PDGFR/EGFR Heterodimer

“…Activation of the PI3K/AKT/mTOR signaling pathway is implicated in hyperproliferation and resistance to apoptosis ( Mercurio et al, 2021 ). Since rSLURP-1 down-regulates this pathway, we studied its influence on cell cycle progression and apoptosis in A549 cells.…”

PI3K/AKT phosphorylation activates ERRα by upregulating PGC‑1α and PGC‑1β in gallbladder cancer

“…The genes in the PI3K/AKT pathway show the highest frequency of aberrant expression in human cancer ( 17 , 32 ). The activated PI3K/AKT pathway functions to enhance the transformation, proliferation and invasion of cancerous cells.…”

“…Therefore, the PI3K/AKT signaling pathway is an ideal target to provide a promising approach for the prevention and clinical therapy of cancer cases. The PI3K/AKT signaling pathway exerts an anti-apoptotic effect mainly by influencing a variety of downstream effector molecules, such as CREB regulated transcription coactivator 1, ribosomal protein S6 kinase B1, S6 Rb and eukaryotic translation initiation factor 4E ( 17 , 32 ). At present, the PI3K/AKT signaling pathway and its related genes can be suppressed by applying gene intervention methods or via the treatment of small-molecule compound drugs.…”

Mitochondrial Metabolism in Melanoma

“…As cell growth through protein synthesis is important for tumor growth, the PI3K/AKT1/mTORC1 pathway, summarized in Figure 7, is often upregulated in cancers including melanoma [55]. For instance, in other skin cancers such as basal and squamous cell carcinoma, the upregulation of the AKT1 signaling pathway has been implicated in tumorigenesis and hyperproliferation [165]. In addition to protein synthesis, mTORC1 has been proposed as a regulator of HIF1A, contributing to aerobic glycolysis [163,166].…”