Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

Cells - Tập 8 Số 8 - Trang 803
Jean Christopher Chamcheu1, Tithi Roy1, Mohammad B. Uddin1, Sergette Banang‐Mbeumi1,2,3, Roxane-Cherille Chamcheu1, Anthony L. Walker1, Yong‐Yu Liu1, Shile Huang4,5
1College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0497, USA
2Division for Research and Innovation, POHOFI Inc., P.O. Box 44067, Madison, WI 53744, USA
3School of Nursing and Allied Health Sciences, Louisiana Delta Community College, Monroe, LA 71203, USA
4Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA
5Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

Templeton, N.S. (2015). Cutaneous Cell-and Gene-Based Therapies for Inherited and Acquired Skin Disorders. Gene and Cell Therapy: Therapeutic Mechanisms and Strategies, CRC Press, Taylor and Francis Group. [4th ed.].

Gonzales, 2017, Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche, Dev. Cell, 43, 387, 10.1016/j.devcel.2017.10.001

Magin, 2007, Structural and regulatory functions of keratins, Exp. Cell Res., 313, 2021, 10.1016/j.yexcr.2007.03.005

Elias, 2013, Update on the structure and function of the skin barrier: Atopic dermatitis as an exemplar of clinical implications, Semin. Cutan. Med. Surg., 32, S21, 10.12788/j.sder.0022

Pullar, J.M., Carr, A.C., and Vissers, M.C.M. (2017). The Roles of Vitamin C in Skin Health. Nutrients, 9.

Segre, 2006, Epidermal barrier formation and recovery in skin disorders, J. Clin. Investig., 116, 1150, 10.1172/JCI28521

Chamcheu, 2011, Keratin gene mutations in disorders of human skin and its appendages, Arch. Biochem. Biophys., 508, 123, 10.1016/j.abb.2010.12.019

Elmets, 2007, Green tea and skin cancer: Photoimmunology, angiogenesis and DNA repair, J. Nutr. Biochem., 18, 287, 10.1016/j.jnutbio.2006.08.004

Eckhart, 2013, Cell death by cornification, Biochim. Biophys. Acta, 1833, 3471, 10.1016/j.bbamcr.2013.06.010

Zhang, 2016, Characterization of Th17 and FoxP3+ Treg Cells in Paediatric Psoriasis Patients, Scand. J. Immunol., 83, 174, 10.1111/sji.12404

Ng, 2018, Proof-of-concept: 3D bioprinting of pigmented human skin constructs, Biofabrication, 10, 25005, 10.1088/1758-5090/aa9e1e

Tharmarajah, 2018, Melanocyte development in the mouse tail epidermis requires the Adamts9 metalloproteinase, Pigment. Cell Melanoma Res., 31, 693, 10.1111/pcmr.12711

Serre, 2018, Intrinsic and extrinsic regulation of human skin melanogenesis and pigmentation, Int. J. Cosmet. Sci., 40, 328, 10.1111/ics.12466

Bertolesi, 2018, Seeing the light to change colour: An evolutionary perspective on the role of melanopsin in neuroendocrine circuits regulating light-mediated skin pigmentation, Pigment. Cell Melanoma Res., 31, 354, 10.1111/pcmr.12678

Moraes, 2018, Melanopsin and rhodopsin mediate UVA-induced immediate pigment darkening: Unravelling the photosensitive system of the skin, Eur. J. Cell Biol., 97, 150, 10.1016/j.ejcb.2018.01.004

Yamaguchi, 2009, Physiological factors that regulate skin pigmentation, BioFactors, 35, 193, 10.1002/biof.29

Yamaguchi, 2009, Regulation of skin pigmentation and thickness by dickkopf 1 (DKK1), J. Investig. Dermatol. Symp. Proc., 14, 73, 10.1038/jidsymp.2009.4

Perez-Sanchez, A., Barrajon-Catalan, E., Herranz-Lopez, M., and Micol, V. (2018). Nutraceuticals for Skin Care: A Comprehensive Review of Human Clinical Studies. Nutrients, 10.

Sagi, 2018, The Impact of the Epithelial–Mesenchymal Transition Regulator Hepatocyte Growth Factor Receptor/Met on Skin Immunity by Modulating Langerhans Cell Migration, Front. Immunol., 9, 517, 10.3389/fimmu.2018.00517

Deckers, 2018, Langerhans Cells: Sensing the Environment in Health and Disease, Front. Immunol., 9, 93, 10.3389/fimmu.2018.00093

Iwamoto, 2018, Langerhans and inflammatory dendritic epidermal cells in atopic dermatitis are tolerized toward TLR2 activation, Allergy, 73, 2205, 10.1111/all.13460

Petersson, 2012, Stem cell dynamics and heterogeneity: Implications for epidermal regeneration and skin cancer, Curr. Med. Chem., 19, 5984, 10.2174/0929867311209065984

Wang, 2010, Progress in epidermal stem cells, Yi Chuan, 32, 198, 10.3724/SP.J.1005.2010.00198

Flores, 2011, Stem cell proliferation in the skin: Alpha-catenin takes over the hippo pathway, Sci. Signal., 4, pe34, 10.1126/scisignal.2002311

Uzarska, 2013, Epidermal stem cells—Biology and potential applications in regenerative medicine, Postępy Biochem., 59, 219

Shen, 2013, Epidermal Stem Cells and Their Epigenetic Regulation, Int. J. Mol. Sci., 14, 17861, 10.3390/ijms140917861

Lavker, 2000, Epidermal stem cells: Properties, markers, and location, Proc. Natl. Acad. Sci. USA, 97, 13473, 10.1073/pnas.250380097

Matsui, 2015, Dissecting the formation, structure and barrier function of the stratum corneum, Int. Immunol., 27, 269, 10.1093/intimm/dxv013

Osawa, 2011, Filaggrin Gene Defects and the Risk of Developing Allergic Disorders, Allergol. Int., 60, 1, 10.2332/allergolint.10-RAI-0270

Sandilands, 2009, Filaggrin in the frontline: Role in skin barrier function and disease, J. Cell Sci., 122, 1285, 10.1242/jcs.033969

Koster, 2009, Making an epidermis, Ann. N. Y. Acad. Sci., 1170, 7, 10.1111/j.1749-6632.2009.04363.x

2012, Information exchanges between cells and extracellular matrix. Influence of aging, Biol. Aujourd’hui, 206, 103

Quan, 2015, Role of Age-Associated Alterations of the Dermal Extracellular Matrix Microenvironment in Human Skin Aging: A Mini-Review, Gerontology, 61, 427, 10.1159/000371708

Watt, 2014, Mammalian skin cell biology: At the interface between laboratory and clinic, Science, 346, 937, 10.1126/science.1253734

Gilchrest, 1999, The Pathogenesis of Melanoma Induced by Ultraviolet Radiation, N. Engl. J. Med., 340, 1341, 10.1056/NEJM199904293401707

Watson, 2016, Ultraviolet Radiation Exposure and Its Impact on Skin Cancer Risk, Semin. Oncol. Nurs., 32, 241, 10.1016/j.soncn.2016.05.005

Miyamura, 2011, The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin, Pigment Cell Melanoma Res., 24, 136, 10.1111/j.1755-148X.2010.00764.x

Jarrett, 2013, UV radiation and the skin, Int. J. Mol. Sci., 14, 12222, 10.3390/ijms140612222

McKenzie, 2015, Ozone depletion and climate change: Impacts on UV radiation, Photochem. Photobiol. Sci., 14, 19

Holick, 2008, Sunlight, UV-radiation, vitamin D and skin cancer: How much sunlight do we need?, Adv. Exp. Med. Biol., 624, 1, 10.1007/978-0-387-77574-6_1

Juzeniene, 2012, Beneficial effects of UV radiation other than via vitamin D production, Dermato-Endocrinology, 4, 109, 10.4161/derm.20013

Gupta, 2013, Ultraviolet Radiation in Wound Care: Sterilization and Stimulation, Adv. Wound Care, 2, 422, 10.1089/wound.2012.0366

Slominski, 2000, Neuroendocrinology of the skin, Endocr. Rev., 21, 457

Diffey, 1991, Solar ultraviolet radiation effects on biological systems, Phys. Med. Boil., 36, 299, 10.1088/0031-9155/36/3/001

Abeyama, 2000, A role for NF-kappaB-dependent gene transactivation in sunburn, J. Clin. Investig., 105, 1751, 10.1172/JCI9745

Leo, 2014, Phytochemical modulation of the Akt/mTOR pathway and its potential use in cutaneous disease, Arch. Dermatol. Res., 306, 861, 10.1007/s00403-014-1480-8

Huang, 2003, Targeting mTOR signaling for cancer therapy, Curr. Opin. Pharmacol., 3, 371, 10.1016/S1471-4892(03)00071-7

Wullschleger, 2006, TOR Signaling in Growth and Metabolism, Cell, 124, 471, 10.1016/j.cell.2006.01.016

Guertin, 2007, Defining the Role of mTOR in Cancer, Cancer Cell, 12, 9, 10.1016/j.ccr.2007.05.008

Laplante, 2012, mTOR signaling in growth control and disease, Cell, 149, 274, 10.1016/j.cell.2012.03.017

Vanhaesebroeck, 2012, PI3K signalling: The path to discovery and understanding, Nat. Rev. Mol. Cell Boil., 13, 195, 10.1038/nrm3290

Lopes, 2012, The mTOR Signalling Pathway in Human Cancer, Int. J. Mol. Sci., 13, 1886, 10.3390/ijms13021886

Saxton, 2017, mTOR Signaling in Growth, Metabolism, and Disease, Cell, 169, 361, 10.1016/j.cell.2017.03.035

Sehgal, 1975, Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization, J. Antibiot., 28, 727, 10.7164/antibiotics.28.727

Sabatini, 1994, RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs, Cell, 78, 35, 10.1016/0092-8674(94)90570-3

Buerger, 2018, Epidermal mTORC1 Signaling Contributes to the Pathogenesis of Psoriasis and Could Serve as a Therapeutic Target, Front. Immunol., 9, 2786, 10.3389/fimmu.2018.02786

Vahidnezhad, 2016, Molecular Genetics of the PI3K-AKT-mTOR Pathway in Genodermatoses: Diagnostic Implications and Treatment Opportunities, J. Investig. Dermatol., 136, 15, 10.1038/JID.2015.331

Huang, 2014, Phosphoinositide-3 Kinase/Protein Kinase-B/Mammalian Target of Rapamycin Pathway in Psoriasis Pathogenesis. A Potential Therapeutic Target?, Acta Derm. Venereol., 94, 371, 10.2340/00015555-1737

Popovic, 2018, mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?, Oxidative Med. Cell. Longev., 2018, 1

Corti, 2019, Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives, Cancer Treat. Rev., 72, 45, 10.1016/j.ctrv.2018.11.001

Cragg, 2013, Natural Products: A Continuing Source of Novel Drug Leads, Biochim. Biophys. Acta, 1830, 3670, 10.1016/j.bbagen.2013.02.008

Newman, 2016, Natural Products as Sources of New Drugs from 1981 to 2014, J. Nat. Prod., 79, 629, 10.1021/acs.jnatprod.5b01055

Strickland, 2015, Targeting Drivers of Melanoma with Synthetic Small Molecules and Phytochemicals, Cancer Lett., 359, 20, 10.1016/j.canlet.2015.01.016

Cronin, 2018, Annual Report to the Nation on the Status of Cancer, part I: National cancer statistics, Cancer, 124, 2785, 10.1002/cncr.31551

Liu, 2018, The Role of Autophagy in the Resistance to BRAF Inhibition in BRAF-Mutated Melanoma, Target. Oncol., 13, 437, 10.1007/s11523-018-0565-2

Wahid, 2018, Recent developments and obstacles in the treatment of melanoma with BRAF and MEK inhibitors, Crit. Rev. Oncol., 125, 84, 10.1016/j.critrevonc.2018.03.005

Shao, Z., Bao, Q., Jiang, F., Qian, H., Fang, Q., and Hu, X. (2015). VS-5584, a Novel PI3K-mTOR Dual Inhibitor, Inhibits Melanoma Cell Growth In Vitro and In Vivo. PLoS ONE, 10.

Syed, 2014, Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: Findings from 3-D melanoma skin equivalents and computational modeling, Biochem. Pharmacol., 89, 349, 10.1016/j.bcp.2014.03.007

Bosbous, 2010, Lentigo Maligna: Diagnosis and Treatment, Clin. Plast. Surg., 37, 35, 10.1016/j.cps.2009.08.006

Broussard, 2018, Melanoma Cell Death Mechanisms, Chonnam Med. J., 54, 135, 10.4068/cmj.2018.54.3.135

Hersey, 2009, Small molecules and targeted therapies in distant metastatic disease, Ann. Oncol., 20, vi35, 10.1093/annonc/mdp254

Yu, 2018, A novel combination treatment against melanoma with NRAS mutation and therapy resistance, EMBO Mol. Med., 10, e8573, 10.15252/emmm.201708573

Caenepeel, 2017, MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor, Oncotarget, 8, 17795, 10.18632/oncotarget.14855

Guo, 2018, KCNQ1OT1 promotes melanoma growth and metastasis, Aging, 10, 632, 10.18632/aging.101418

Luan, 2016, Long non-coding RNA MALAT1 acts as a competing endogenous RNA to promote malignant melanoma growth and metastasis by sponging miR-22, Oncotarget, 7, 63901, 10.18632/oncotarget.11564

Luan, 2017, Long non-coding RNA HOTAIR acts as a competing endogenous RNA to promote malignant melanoma progression by sponging miR-152-3p, Oncotarget, 8, 85401, 10.18632/oncotarget.19910

Karbowniczek, 2008, mTOR Is Activated in the Majority of Malignant Melanomas, J. Investig. Dermatol., 128, 980, 10.1038/sj.jid.5701074

Molhoek, 2005, Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin, J. Transl. Med., 3, 39, 10.1186/1479-5876-3-39

Rao, 2018, Phase II Study of Everolimus in Metastatic Malignant Melanoma (NCCTG-N0377, Alliance), Oncologist, 23, 887-e94

Niessner, 2017, Combined activity of temozolomide and the mTOR inhibitor temsirolimus in metastatic melanoma involves DKK1, Exp. Dermatol., 26, 598, 10.1111/exd.13372

Rangwala, 2014, Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma, Autophagy, 10, 1391, 10.4161/auto.29119

Hainsworth, 2010, Bevacizumab and everolimus in the treatment of patients with metastatic melanoma: A phase 2 trial of the Sarah Cannon Oncology Research Consortium, Cancer, 116, 4122, 10.1002/cncr.25320

Kolev, 2015, PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells, Cancer Res., 75, 446, 10.1158/0008-5472.CAN-14-1223

Hutchinson, 2015, Skin cancer. Golden age of melanoma therapy, Nat. Rev. Clin. Oncol., 12, 1, 10.1038/nrclinonc.2014.219

Webster, 2014, The malignant melanoma landscape, Nat. Rev. Drug Discov. Engl., 13, 491, 10.1038/nrd4326

Schadendorf, 2014, Melanoma in 2013: Melanoma—The run of success continues, Nat. Rev. Clin. Oncol., 11, 75, 10.1038/nrclinonc.2013.246

Mi, 2014, 4′,6-dihydroxy-4-methoxyisoaurone inhibits the HIF-1alpha pathway through inhibition of Akt/mTOR/p70S6K/4E-BP1 phosphorylation, J. Pharmacol. Sci., 125, 193, 10.1254/jphs.13273FP

Wang, 2014, SKLB-M8 induces apoptosis through the AKT/mTOR signaling pathway in melanoma models and inhibits angiogenesis with decrease of ERK1/2 phosphorylation, J. Pharmacol. Sci., 126, 198, 10.1254/jphs.14077FP

Oudart, 2016, The anti-tumor NC1 domain of collagen XIX inhibits the FAK/PI3K/Akt/mTOR signaling pathway through alphavbeta3 integrin interaction, Oncotarget, 7, 1516, 10.18632/oncotarget.6399

Lee, 2015, FAK signaling in human cancer as a target for therapeutics, Pharmacol. Ther., 146, 132, 10.1016/j.pharmthera.2014.10.001

Sulzmaier, 2014, FAK in cancer: Mechanistic findings and clinical applications, Nat. Rev. Cancer, 14, 598, 10.1038/nrc3792

Si, 2012, Major Response to Everolimus in Melanoma With Acquired Imatinib Resistance, J. Clin. Oncol., 30, e37, 10.1200/JCO.2011.37.9644

Paquet, 2015, Hedgehog-and mTOR-targeted therapies for advanced basal cell carcinomas, Future Oncol., 11, 2997, 10.2217/fon.15.181

Kapoor, 2012, Erufosine simultaneously induces apoptosis and autophagy by modulating the Akt–mTOR signaling pathway in oral squamous cell carcinoma, Cancer Lett., 319, 39, 10.1016/j.canlet.2011.12.032

Ding, 2018, GDC-0084 inhibits cutaneous squamous cell carcinoma cell growth, Biochem. Biophys. Res. Commun., 503, 1941, 10.1016/j.bbrc.2018.07.139

Nguyen, 2011, Melanoma chemoprevention in skin reconstructs and mouse xenografts using isoselenocyanate-4, Cancer Prev. Res., 4, 248, 10.1158/1940-6207.CAPR-10-0106

Kannan, 2016, Dual mTOR inhibitor MLN0128 suppresses Merkel cell carcinoma (MCC) xenograft tumor growth, Oncotarget, 7, 6576, 10.18632/oncotarget.5878

Cassler, 2016, Merkel Cell Carcinoma Therapeutic Update, Curr. Treat. Options Oncol., 17, 36, 10.1007/s11864-016-0409-1

Villani, 2019, Merkel Cell Carcinoma: Therapeutic Update and Emerging Therapies, Dermatol. Ther., 9, 209, 10.1007/s13555-019-0288-z

Calero, 2017, Synergistic anti-tumor effect of 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 on human melanoma, Cancer Lett., 406, 1, 10.1016/j.canlet.2017.07.021

Lin, 2015, Effect of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against human Merkel cell carcinoma MKL-1 cells, Oncol. Lett., 10, 3663, 10.3892/ol.2015.3791

Chung, 2011, Melanoma prevention using topical PBISe, Cancer Prev. Res., 4, 935, 10.1158/1940-6207.CAPR-10-0202

Hou, 2007, An activated mTOR/p70S6K signaling pathway in esophageal squamous cell carcinoma cell lines and inhibition of the pathway by rapamycin and siRNA against mTOR, Cancer Lett., 253, 236, 10.1016/j.canlet.2007.01.026

Werzowa, 2011, Vertical Inhibition of the mTORC1/mTORC2/PI3K Pathway Shows Synergistic Effects against Melanoma In Vitro and In Vivo, J. Investig. Dermatol., 131, 495, 10.1038/jid.2010.327

Chong, 2012, Cutting Edge in Medical Management of Cutaneous Oncology, Semin. Cutan. Med. Surg., 31, 140, 10.1016/j.sder.2012.03.002

So, 2014, PI3K-AKT signaling is a downstream effector of retinoid prevention of murine basal cell carcinogenesis, Cancer Prev. Res., 7, 407, 10.1158/1940-6207.CAPR-13-0304

Wu, 2014, Tazarotene Induces Apoptosis in Human Basal Cell Carcinoma via Activation of Caspase-8/t-Bid and the Reactive Oxygen Species-Dependent Mitochondrial Pathway, DNA Cell Boil., 33, 652, 10.1089/dna.2014.2366

Velho, 2012, Metastatic melanoma—A review of current and future drugs, Drugs Context, 2012, 1, 10.7573/dic.212242

Lin, 2014, Chronic mTOR activation promotes cell survival in Merkel cell carcinoma, Cancer Lett., 344, 272, 10.1016/j.canlet.2013.11.005

Liang, 2017, Itraconazole exerts its anti-melanoma effect by suppressing Hedgehog, Wnt, and PI3K/mTOR signaling pathways, Oncotarget, 8, 28510, 10.18632/oncotarget.15324

Head, 2015, Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells, Proc. Natl. Acad. Sci. USA, 112, E7276, 10.1073/pnas.1512867112

Zou, 2017, Targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin squamous cell carcinoma cell growth in vitro and in vivo, Biochem. Biophys. Res. Commun., 490, 385, 10.1016/j.bbrc.2017.06.052

Sweetlove, 2015, Inhibitors of pan-PI3K Signaling Synergize with BRAF or MEK Inhibitors to Prevent BRAF-Mutant Melanoma Cell Growth, Front. Oncol., 5, 135, 10.3389/fonc.2015.00135

Polini, 2019, Circulating cell-free microRNAs in cutaneous melanoma staging and recurrence or survival prognosis, Pigment. Cell Melanoma Res., 32, 486, 10.1111/pcmr.12755

Li, 2019, miR-224-5p inhibits proliferation, migration, and invasion by targeting PIK3R3/AKT3 in uveal melanoma, J. Cell. Biochem., 120, 12412, 10.1002/jcb.28507

Jiang, 2018, miR-25 Promotes Melanoma Progression by regulating RNA binding motif protein 47, Med. Sci., 34, 59

Meng, 2017, Clinical significance of miR-138 in patients with malignant melanoma through targeting of PDK1 in the PI3K/AKT autophagy signaling pathway, Oncol. Rep., 38, 1655, 10.3892/or.2017.5838

Micevic, 2016, DNMT3b modulates melanoma growth by controlling levels of mTORC2 component RICTOR, Cell Rep., 14, 2180, 10.1016/j.celrep.2016.02.010

Schmidt, 2018, Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis12, Neoplasia, 20, 1198, 10.1016/j.neo.2018.10.001

Damsky, 2015, mTORC1 activation blocks BrafV600E-induced growth-arrest, but is insufficient for melanoma formation, Cancer Cell, 27, 41, 10.1016/j.ccell.2014.11.014

Gil, 2017, Treatment of melanoma with selected inhibitors of signaling kinases effectively reduces proliferation and induces expression of cell cycle inhibitors, Med. Oncol., 35, 7

Sikora, 2010, Targeted inhibition of inducible nitric oxide synthase inhibits growth of human melanoma in vivo and synergizes with chemotherapy, Clin. Cancer Res., 16, 1834, 10.1158/1078-0432.CCR-09-3123

Ernst, 2005, Phase II Study of Perifosine in Previously Untreated Patients with Metastatic Melanoma, Investig. New Drugs, 23, 569, 10.1007/s10637-005-1157-4

Jung, 2014, The P110 subunit of PI3-K is a therapeutic target of acacetin in skin cancer, Carcinogenesis, 35, 123, 10.1093/carcin/bgt266

Chien, 2011, Acacetin inhibits the invasion and migration of human non-small cell lung cancer A549 cells by suppressing the p38alpha MAPK signaling pathway, Mol. Cell. Biochem., 350, 135, 10.1007/s11010-010-0692-2

Shin, 2008, Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway, Exp. Mol. Med., 40, 486, 10.3858/emm.2008.40.5.486

Wang, 2010, Evodiamine-induced human melanoma A375-S2 cell death was mediated by PI3K/Akt/caspase and Fas-L/NF-kappaB signaling pathways and augmented by ubiquitin-proteasome inhibition, Toxicol. In Vitro, 24, 898, 10.1016/j.tiv.2009.11.019

Chen, 2017, Reprogramming induced by isoliquiritigenin diminishes melanoma cachexia through mTORC2-AKT-GSK3beta signaling, Oncotarget, 8, 34565, 10.18632/oncotarget.16655

Lim, H.N., Baek, S.B., and Jung, H.J. (2019). Bee Venom and Its Peptide Component Melittin Suppress Growth and Migration of Melanoma Cells via Inhibition of PI3K/AKT/mTOR and MAPK Pathways. Molecules, 24.

Lai, 2018, Panduratin A induces protective autophagy in melanoma via the AMPK and mTOR pathway, Phytomedicine, 42, 144, 10.1016/j.phymed.2018.03.027

Zou, N., Wei, Y., Li, F., Yang, Y., Cheng, X., and Wang, C. (2017). The inhibitory effects of compound Muniziqi granule against B16 cells and harmine induced autophagy and apoptosis by inhibiting Akt/mTOR pathway. BMC Complement. Altern. Med., 17.

Sun, 2018, Sinomenine inhibits the growth of melanoma by enhancement of autophagy via PI3K/AKT/mTOR inhibition, Drug Des. Dev. Ther., 12, 2413, 10.2147/DDDT.S155798

Hosseini, 2012, Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax, Biochem. Pharmacol., 83, 489, 10.1016/j.bcp.2011.11.027

Meyskens, 2016, Molecular mechanisms of flavonoids in melanin synthesis and the potential for the prevention and treatment of melanoma, Mol. Nutr. Food Res., 60, 1264, 10.1002/mnfr.201500822

Pal, 2016, Phytochemicals for the Management of Melanoma, Mini-Rev. Med. Chem., 16, 953, 10.2174/1389557516666160211120157

Adhami, 2012, Dietary flavonoid fisetin: A novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management, Biochem. Pharmacol., 84, 1277, 10.1016/j.bcp.2012.07.012

Syed, 2011, Botanicals for the prevention and treatment of cutaneous melanoma, Pigment. Cell Melanoma Res., 24, 688, 10.1111/j.1755-148X.2011.00851.x

Govindarajan, 2007, Overexpression of Akt converts radial growth melanoma to vertical growth melanoma, J. Clin. Investig., 117, 719, 10.1172/JCI30102

Pearce, 2010, Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1), Biochem. J., 431, 245, 10.1042/BJ20101024

Sechi, 2018, Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: Insights from in vitro and in vivo melanoma models, Sci. Rep., 8, 15726, 10.1038/s41598-018-33879-w

Pal, 2015, Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells, Oncotarget, 6, 28296, 10.18632/oncotarget.5064

Zhao, 2016, Curcumin induces autophagy, inhibits proliferation and invasion by downregulating AKT/mTOR signaling pathway in human melanoma cells, Oncol. Rep., 35, 1065, 10.3892/or.2015.4413

Rozzo, 2013, Molecular changes induced by the curcumin analogue D6 in human melanoma cells, Mol. Cancer, 12, 37, 10.1186/1476-4598-12-37

Wang, 2014, Resveratrol Triggers Protective Autophagy Through the Ceramide/Akt/mTOR Pathway in Melanoma B16 Cells, Nutr. Cancer, 66, 435, 10.1080/01635581.2013.878738

Bhattacharya, 2011, Resveratrol modulates the malignant properties of cutaneous melanoma through changes in the activation and attenuation of the antiapoptotic protooncogenic protein Akt/PKB, Melanoma Res., 21, 180, 10.1097/CMR.0b013e3283456dfc

Aggarwal, 2004, Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies, Anticancer Res., 24, 2783

Kaushik, 2012, Honokiol induces cytotoxic and cytostatic effects in malignant melanoma cancer cells, Am. J. Surg., 204, 868, 10.1016/j.amjsurg.2012.09.001

Prieto, 2015, Natural products with therapeutic potential in melanoma metastasis, Nat. Prod. Rep., 32, 1170, 10.1039/C4NP00130C

Hambright, 2015, Inhibition of PI3K/AKT/mTOR axis disrupts oxidative stress-mediated survival of melanoma cells, Oncotarget, 6, 7195, 10.18632/oncotarget.3131

Gong, 2014, STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth, Oncotarget, 5, 2529, 10.18632/oncotarget.1810

Huang, 2018, Honokiol inhibits in vitro and in vivo growth of oral squamous cell carcinoma through induction of apoptosis, cell cycle arrest and autophagy, J. Cell. Mol. Med., 22, 1894, 10.1111/jcmm.13474

Surdu, 2014, Non-melanoma skin cancer: Occupational risk from UV light and arsenic exposure, Rev. Environ. Health, 29, 255, 10.1515/reveh-2014-0040

Burton, 2016, Cutaneous Squamous Cell Carcinoma: A Review of High-Risk and Metastatic Disease, Am. J. Clin. Dermatol., 17, 491, 10.1007/s40257-016-0207-3

Cohen, 2018, Basal Cell Carcinoma: A Patient and Physician’s Experience, Dermatol. Ther., 8, 329, 10.1007/s13555-018-0245-2

Wong, 2003, Basal cell carcinoma, BMJ, 327, 794, 10.1136/bmj.327.7418.794

Marzuka, 2015, Basal Cell Carcinoma: Pathogenesis, Epidemiology, Clinical Features, Diagnosis, Histopathology, and Management, Yale J. Boil. Med., 88, 167

Rogers, 2015, Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012, JAMA Dermatol., 151, 1081, 10.1001/jamadermatol.2015.1187

Eisemann, 2014, Non-Melanoma Skin Cancer Incidence and Impact of Skin Cancer Screening on Incidence, J. Investig. Dermatol., 134, 43, 10.1038/jid.2013.304

Guy, 2015, Vital Signs: Melanoma Incidence and Mortality Trends and Projections—United States, 1982–2030, MMWR. Morb. Mortal. Wkly. Rep., 64, 591

Rigel, 2008, Cutaneous ultraviolet exposure and its relationship to the development of skin cancer, J. Am. Acad. Dermatol., 58, S129, 10.1016/j.jaad.2007.04.034

Tarallo, 2008, Metatypical basal cell carcinoma: A clinical review, J. Exp. Clin. Cancer Res., 27, 65, 10.1186/1756-9966-27-65

Athar, 2014, Sonic Hedgehog Signaling in Basal Cell Nevus Syndrome, Cancer Res., 74, 4967, 10.1158/0008-5472.CAN-14-1666

Noubissi, 2014, Role of CRD-BP in the growth of human Basal Cell Carcinoma Cells, J. Investig. Dermatol., 134, 1718, 10.1038/jid.2014.17

Chamcheu, J.C., Rady, I., Chamcheu, R.-C.N., Siddique, A.B., Bloch, M.B., Mbeumi, S.B., Babatunde, A.S., Uddin, M.B., Noubissi, F.K., and Jurutka, P.W. (2018). Graviola (Annona muricata) Exerts Anti-Proliferative, Anti-Clonogenic and Pro-Apoptotic Effects in Human Non-Melanoma Skin Cancer UW-BCC1 and A431 Cells In Vitro: Involvement of Hedgehog Signaling. Int. J. Mol. Sci., 19.

Kasper, 2012, Basal cell carcinoma—Molecular biology and potential new therapies, J. Clin. Investig., 122, 455, 10.1172/JCI58779

Bakshi, 2017, Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond, Mol. Carcinog., 56, 2543, 10.1002/mc.22690

Alter, 2015, Current diagnosis and treatment of basal cell carcinoma, J. Dtsch. Dermatol. Ges., 13, 863

Tsubamoto, 2017, Repurposing itraconazole as an anticancer agent, Oncol. Lett., 14, 1240, 10.3892/ol.2017.6325

Alam, 2001, Cutaneous squamous-cell carcinoma, N. Engl. J. Med., 344, 975, 10.1056/NEJM200103293441306

Lansbury, 2013, Interventions for non-metastatic squamous cell carcinoma of the skin: Systematic review and pooled analysis of observational studies, BMJ, 347, f6153, 10.1136/bmj.f6153

Agamia, 2016, Skin expression of mammalian target of rapamycin and forkhead box transcription factor O1, and serum insulin-like growth factor-1 in patients with acne vulgaris and their relationship with diet, Br. J. Dermatol., 174, 1299, 10.1111/bjd.14409

Gurney, 2014, Management of regional metastatic disease in head and neck cutaneous malignancy.1. Cutaneous squamous cell carcinoma, Br. J. Oral Maxillofac. Surg., 52, 294, 10.1016/j.bjoms.2014.01.015

Azimi, 2018, Differential proteomic analysis of actinic keratosis, Bowen’s disease and cutaneous squamous cell carcinoma by label-free LC–MS/MS, J. Dermatol. Sci., 91, 69, 10.1016/j.jdermsci.2018.04.006

Plasmeijer, 2018, Azathioprine to mycophenolate mofetil transition and risk of squamous cell carcinoma after lung transplantation, J. Hear. Lung Transplant., 37, 853, 10.1016/j.healun.2018.03.012

Lewis, 2012, A Phase II Study of Gefitinib for Aggressive Cutaneous Squamous Cell Carcinoma of the Head and Neck, Clin. Cancer Res., 18, 1435, 10.1158/1078-0432.CCR-11-1951

Karayannopoulou, 2013, Differential expression of p-mTOR in cutaneous basal and squamous cell carcinomas likely explains their different response to mTOR inhibitors in organ-transplant recipients, Anticancer Res., 33, 3711

Wu, 2018, The Expression and Prognostic Impact of the PI3K/AKT/mTOR Signaling Pathway in Advanced Esophageal Squamous Cell Carcinoma, Technol. Cancer Res. Treat., 17, 1533033818758772, 10.1177/1533033818758772

Euvrard, 2003, Skin Cancers after Organ Transplantation, N. Engl. J. Med., 348, 1681, 10.1056/NEJMra022137

Chen, 2009, Activation of the mammalian target of rapamycin signalling pathway in epidermal tumours and its correlation with cyclin-dependent kinase 2, Br. J. Dermatol., 160, 442, 10.1111/j.1365-2133.2008.08903.x

Monaco, 2009, The Role of mTOR Inhibitors in the Management of Posttransplant Malignancy, Transplant., 87, 157, 10.1097/TP.0b013e318193886e

Einspahr, 2012, Functional protein pathway activation mapping of the progression of normal skin to squamous cell carcinoma, Cancer Prev. Res., 5, 403, 10.1158/1940-6207.CAPR-11-0427

Massarelli, 2015, Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma, Ann. Oncol., 26, 1476, 10.1093/annonc/mdv194

Schrama, 2012, Merkel cell carcinoma: Recent insights and new treatment options, Curr. Opin. Oncol., 24, 141, 10.1097/CCO.0b013e32834fc9fe

Shuda, 2011, Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator, J. Clin. Investig., 121, 3623, 10.1172/JCI46323

Fahmy, 2019, Desmoplastic fibroma associated with tuberous sclerosis: Case report and literature review, Oral Surg. Oral Med. Oral Pathol. Oral Radiol., 128, e92, 10.1016/j.oooo.2019.03.008

Ekure, 2019, Tuberous sclerosis in a patient from Nigeria, Am. J. Med. Genet. Part A, 179, 1423, 10.1002/ajmg.a.61194

Curatolo, 2008, Tuberous sclerosis, Lancet, 372, 657, 10.1016/S0140-6736(08)61279-9

Islam, 2015, Tuberous sclerosis complex, Handbook of Clinical Neurology, Volume 132, 97, 10.1016/B978-0-444-62702-5.00006-8

Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., and Stephens, K. (1993). Tuberous Sclerosis Complex, Oxford University Press.

Wei, 2018, Trend of seizure remission in patients with tuberous sclerosis complex: A retrospective medical review, J. Chin. Med. Assoc., 81, 724, 10.1016/j.jcma.2018.02.001

Volpi, 2019, Tuberous sclerosis complex: New insights into clinical and therapeutic approach, J. Nephrol., 32, 355, 10.1007/s40620-018-0547-6

Crino, 2006, The tuberous sclerosis complex, N. Engl. J. Med., 355, 1345, 10.1056/NEJMra055323

Curatolo, 2012, mTOR Inhibitors in Tuberous Sclerosis Complex, Curr. Neuropharmacol., 10, 404, 10.2174/157015912804499537

Adil, A., and Singh, A.K. (2019). Neurofibromatosis Type 1 (Von Recklinghausen), StatPearls Publishing.

Treichel, A.M., Hamieh, L., Nathan, N.R., Tyburczy, M.E., Wang, J.-A., Oyerinde, O., Raiciulescu, S., Julien-Williams, P., Jones, A.M., and Gopalakrishnan, V. (2019). Phenotypic distinctions between mosaic forms of tuberous sclerosis complex. Genet. Med., 1.

Giannikou, K., Lasseter, K.D., Grevelink, J.M., Tyburczy, M.E., Dies, K.A., Zhu, Z., Hamieh, L., Wollison, B.M., Thorner, A.R., and Ruoss, S.J. (2019). Low-level mosaicism in tuberous sclerosis complex: Prevalence, clinical features, and risk of disease transmission. Genet. Med., 1.

Leducq, 2019, Topical use of mammalian target of rapamycin inhibitors in dermatology: A systematic review with meta-analysis, J. Am. Acad. Dermatol., 80, 735, 10.1016/j.jaad.2018.10.070

Combes, 2018, Population pharmacokinetics–pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex, J. Pharmacokinet. Pharmacodyn., 45, 707, 10.1007/s10928-018-9600-2

Weidinger, 2016, Atopic dermatitis, Lancet, 387, 1109, 10.1016/S0140-6736(15)00149-X

Boehncke, 2015, Psoriasis, Lancet, 386, 983, 10.1016/S0140-6736(14)61909-7

Desmet, 2017, Glucocorticoid receptors: Finding the middle ground, J. Clin. Investig., 127, 1136, 10.1172/JCI88886

Das, 2012, Role of nutraceuticals in human health, J. Food Sci. Technol., 49, 173, 10.1007/s13197-011-0269-4

Proksch, 2014, Oral intake of specific bioactive collagen peptides reduces skin wrinkles and increases dermal matrix synthesis, Skin Pharmacol. Physiol., 27, 113, 10.1159/000355523