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.
Highlights
Phosphatidylinositol 3-kinase (PI3K) represents a family of kinases which play vital roles in mammalian cells by regulating proliferation, growth, and survival initiated by many growth and survival factors [1, 2]
Aberrant PI3K/AKT/mammalian target of rapamycin (mTOR) signaling is observed in pathological skin, in particular in cutaneous cancer, as well as in chronic inflammatory diseases, such as psoriasis and atopic dermatitis (AD)
We provide an update on the latest research efforts on the roles and mechanisms of PI3K/AKT/mTOR molecular axis in regulating hyperproliferative processes in the epidermal compartment of diseased skin
Summary
Phosphatidylinositol 3-kinase (PI3K) represents a family of kinases which play vital roles in mammalian cells by regulating proliferation, growth, and survival initiated by many growth and survival factors [1, 2]. Zhao and colleagues investigated on the cutaneous expression of a series of pro-proliferative proteins, including AKT mediators, in transgenic mice expressing the tyrosine kinase Fyn, a model spontaneously forming keratotic lesions, scaly plaques, and large tumors, resembling AKs, carcinoma in situ (SCIS), and SCCs, respectively [98] They found increased levels of phosphorylated PDK1, together with STAT3 and ERK1/2, in both precancerous and SCCs lesions, compared with nonlesional epidermis. Our group reported a strong expression of phosphorylated AKT in lesional psoriatic skin and in cytokine-activated keratinocytes derived from patients affected by psoriasis [53]. In the three hyperproliferative skin conditions, PI3K/AKT/mTOR signaling is hyperactivated and involved in pathogenic processes (hyperproliferation, epidermal differentiation, inflammation, apoptosis, and senescence) depending on the disease context. 200 μm [Phospho-AKT stainings have been retrieved from Ref. [53, 73]]
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