The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.

Inflammatory skin diseases (ISDs) such as psoriasis and allergic contact dermatitis affects millions of people and poses a major public health burden. Aberrant cytokine production is a prominent characteristic of ISDs, although the molecular mechanisms underlying the imbalance between pro-and anti-inflammatory gene expression remain underexplored. Cterminal-binding protein (CtBP) 1 and 2 are transcriptional coregulators that repress diverse cellular processes. Our recently studies have uncovered a previously unrecognized proinflammatory role of CtBP in skin inflammation. CtBP1 overexpression in transgenic mouse keratinocytes causes a psoriasis-like phenotype including increased epidermal proliferation, immunocyte infiltration and proinflammatory cytokine expression in skin. Expression of the CtBPs is elevated in both human psoriatic skin lesions and the inflamed skin of two mouse ISD models, the imiquimod-induced psoriasis and the DNFB-induced contact hypersensitivity. Keratinocytes stimulated by imiquimod or DNFB exhibit transactivation of CtBP2 and CtBP-controlled proinflammatory genes that is accompanied by increased recruitment of CtBPs to the target promoters. Furthermore, we demonstrate that distinct CtBP-specific inhibitors can effectively suppress the expression of the CtBP target genes by evicting CtBPs from their target promoters and relieve symptoms of skin inflammation with topical treatment in both mouse ISD models. Together, these findings indicate that the CtBPs can promote skin inflammation by transactivating a select set of proinflammatory genes and suggest new avenues for therapeutic modulation of inflammation and immune responses in ISDs.

Melanoma and nonmelanoma skin cancer are the most lethal and commonest forms of skin cancers affecting one fifth of the US population. With the aim of identifying new lead compounds as starting point for attaining cost effective therapies, a small library of about 90 molecules was screened in vitro against A375, SKMEL28, A431, SCC12 skin cancer cell lines. About 35 of them, mainly dihydroquinolines, CC and CN linked biphenyls, and substituted methyl gallate or aniline derivatives, displayed low micromolar range activities, primarily against the A431 and SCC12 squamous carcinoma cell lines, with only a handful of these compounds displaying any activity against the A375 and SKMEL28 melanoma cell lines. Compounds 11 (A431: IC50 = 5.0 lower case Greek muM, SCC12: IC50 = 2.9 lower case Greek muM, SKMEL-28: IC50 = 4.9 lower case Greek muM, A375: IC50 = 6.7 lower case Greek muM) and 13 (A431: IC50 = 5.0 lower case Greek muM, SCC-12: IC50 = 3.3 lower case Greek muM, SKMEL-28: IC50 = 13.8 lower case Greek muM, A375: IC50 = 17.1 lower case Greek muM) were the most active across all these cell lines. Furthermore, many of the hit compounds showed little to no activity against mammalian nontumorigenic immortalized HaCaT cells, with a far better selectivity index than cisplatin (a well-known anticancer agent used as a positive control). Compounds 11 and 13 significantly and dose dependently induced apoptosis of SCC12 and SKMEL28 cells as evidenced by the downregulation of Bcl2 and upregulation of Bax protein expression levels, and by cleaved caspase 3, caspase 9 and PARP levels. Both agents also significantly reduced scratch wound healing, colony formation, and activated expression levels of major cancer molecular targets such as RSK/AKT/ERK1/2 and S6K1. To provide a better attribute profile for each of the hit molecules, in silico target(s) prediction, pharmacokinetic and ADMET studies are also reported, together with some preliminary structure activity relationship outlines. The SwissTargetPrediction web-based tool identified CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, as likely targets for these hit compounds. Furthermore, the SwissADME web_tool predicted these compounds to exhibit high GI tract absorption, good skin permeation, and a viable biodegradability profile. To summarize, these data highlight the promising anticancer potential of these small molecules leads, warranting further investigation and/or optimization towards obtaining clinical candidates for combatting both melanoma and nonmelanoma skin cancers.

Psoriasis is a chronic autoimmune inflammatory skin disorder characterized by epidermal hyperplasia and aberrant immune response. In addition to aberrant cytokine production, psoriasis is associated with activation of the Akt/mTOR pathway. mTOR/S6K1 regulates T-lymphocyte activation and migration, keratinocytes proliferation and is upregulated in psoriatic lesions. Several drugs that target Th1/Th17 cytokines or their receptors have been approved for treating psoriasis in humans with variable results necessitating improved therapies. Fisetin, a natural dietary polyphenol with anti-oxidant and anti-proliferative properties, covalently binds mTOR/S6K1. The effects of fisetin on psoriasis and its underlying mechanisms have not been clearly defined. Here, we evaluated the immunomodulatory effects of fisetin on Th1/Th17-cytokine-activated adult human epidermal keratinocytes (HEKa) and anti-CD3/CD28-stimulated inflammatory CD4+ T cells and compared these activities with those of rapamycin (an mTOR inhibitor). Transcriptomic analysis of HEKa revealed 12,713 differentially expressed genes (DEGs) in the fisetin-treated group compared to 7,374 DEGs in the rapamycin-treated group, both individually compared to a cytokine treated group. Gene ontology analysis revealed enriched functional groups related to PI3K/Akt/mTOR signaling pathways, psoriasis, and epidermal development. Using in silico molecular modeling, we observed a high binding affinity of fisetin to IL-17A. In vitro, fisetin significantly inhibited mTOR activity, increased the expression of autophagy markers LC3A/B and Atg5 in HEKa cells and suppressed the secretion of IL-17A by activated CD4+ T lymphocytes or T lymphocytes co-cultured with HEKa. Topical administration of fisetin in an imiquimod (IMQ)-induced mouse psoriasis model exhibited a better effect than rapamycin in reducing psoriasis-like inflammation and Akt/mTOR phosphorylation and promoting keratinocyte differentiation and autophagy in mice skin lesions. Fisetin also significantly inhibited T-lymphocytes and F4/80+ macrophage infiltration into skin. We conclude that fisetin potently inhibits IL-17A and the Akt/mTOR pathway and promotes keratinocyte differentiation and autophagy to alleviate IMQ-induced psoriasis-like disease in mice. Altogether, our findings suggest fisetin as a potential treatment for psoriasis and possibly other inflammatory skin diseases.

Alopecia areata (AA) is an autoimmune disease of the hair follicle (HF). Central to the disease is IFNg which accumulates in HFs leading to a Th1 autoimmune response, failure of the hair bulb immune privilege (IP), premature catagen induction followed by HF dystrophy. Currently, combination of steroid and minoxidil is considered to be the first line of treatment, providing protection through the suppression of inflammation. Some JAK inhibitors are under clinical trials for AA and demonstrate fairly good efficacy. However, systemic administration of JAK inhibitors has potential side-effects due to its broad immunosuppressive activities. Therefore, the selective inhibition of IFNg could provide a more effective treatment of AA with fewer side-effects. Here, we investigated whether TAGCyx's proprietary ssDNA aptamer TAGX-0003, characterized by high affinity against IFNg (Kd¼33pM), protects HFs from experimentally induced IP collapse and rescues HFs from AA-like phenotype in the humanized mouse model for AA. Systemic administration of 0.3 or 3nM TAGX-0003 significantly inhibited 100IU/ml IFNg-induced STAT1 phosphorylation in human HF organ culture.In the humanized mouse model of AA, intradermal injection of TAGX-0003 drastically reduced MHC class I and II expression in and around hair bulbs, rescued HFs from IP collapse and significantly promoted hair regrowth during the dose escalating period (12-300nM). Moreover, TAGX-0003 significantly reduced peri-and intra-follicular CD8 positive T cells around the bulb. Further, melanogenesis was clearly observed by TAGX-0003 treatment. In conclusion, TAGX-0003 prominently protected HFs from IP collapse, potentially preventing disease relapse, and it could be developed as a potent medicine for treatment of AA.