Juglanin ameliorates UVB‑induced skin carcinogenesis via anti‑inflammatory and proapoptotic effects in vivo and in vitro

Hou,Gui‑Rong; Zeng,Kang; Lan,Hai‑Mei; Wang,Qi

doi:10.3892/ijmm.2018.3601

Juglanin ameliorates UVB‑induced skin carcinogenesis via anti‑inflammatory and proapoptotic effects in vivo and in vitro

Authors:
- Gui‑Rong Hou
- Kang Zeng
- Hai‑Mei Lan
- Qi Wang
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Affiliations: Department of Dermatology, Nanfang Hospital, Nanfang Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: March 29, 2018 https://doi.org/10.3892/ijmm.2018.3601
Pages: 41-52

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Abstract

Ultraviolet (UV) radiation induces skin injury, and is associated with the development and formation of melanoma, which is a highly lethal form of skin cancer. Juglanin is a natural product, which is predominantly extracted from Polygonum aviculare, and is considered a functional component among its various compounds. Juglanin has been reported to exert marked protective effects in various diseases via the inhibition of inﬂammation and tumor cell growth. The present study aimed to explore the effects of juglanin on human skin cancer induced by UV and to reveal the underlying molecular mechanism. In the present study, immunohistochemical analysis, western blot analysis, RT-qPCR analysis and flow cytometry assays were mainly used in vivo and/or in vitro. The results indicated that in mice, UVB exposure increased susceptibility to carcinogens, and accelerated disease pathogenesis. Conversely, juglanin was able to ameliorate this condition via inhibition of inflammation, suppression of cell proliferation and induction of apoptosis via p38/c‑Jun N‑terminal kinase (JNK) blockage, nuclear factor (NF)‑κB inactivation and caspase stimulation in vivo. In addition, in vitro, the present study demonstrated that treatment of UVB‑stimulated B16F10 melanoma cells with juglanin resulted in a dose‑dependent decrease in cell viability, as well as increased apoptosis via the upregulation of caspase expression and poly (ADP‑ribose) polymerase cleavage. In addition, juglanin markedly attenuated p38/JNK signaling, inactivated the phosphoinositide 3‑kinase/protein kinase B pathway and suppressed UVB‑induced NF‑κB activation. Taken together, these results indicated the possibility of applying juglanin in combination with UVB as a potential therapeutic strategy for preventing skin cancer.

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1	D'Orazio J, Jarrett S, Amaro-Ortiz A and Scott T: UV radiation and the skin. Int J Mol Sci. 14:12222–12248. 2013. View Article : Google Scholar : PubMed/NCBI
2	Chen ST, Geller AC and Tsao H: Update on the epidemiology of melanoma. Curr Dermatol Rep. 2:24–34. 2013. View Article : Google Scholar : PubMed/NCBI
3	Saladi RN and Persaud AN: The causes of skin cancer: a comprehensive review. Drugs Today (Barc). 41:37–53. 2005. View Article : Google Scholar
4	Balk SJ; Section on Dermatology; Council on Environmental Health: Ultraviolet radiation: a hazard to children and adolescents. Pediatrics. 127:588–597. 2011. View Article : Google Scholar : PubMed/NCBI
5	Zhou GY, Yi YX, Jin LX, Lin W, Fang PP, Lin XZ, Zheng Y and Pan CW: The protective effect of juglanin on fructose-induced hepatitis by inhibiting inflammation and apoptosis through TLR4 and JAK2/STAT3 signaling pathways in fructose-fed rats. Biomed Pharmacother. 81:318–328. 2016. View Article : Google Scholar : PubMed/NCBI
6	Yang HH, Hwangbo K, Zheng MS, Son JK, Kim HY, Baek SH, Choi HC, Park SY and Kim JR: Inhibitory effects of juglanin on cellular senescence in human dermal fibroblasts. J Nat Med. 68:473–480. 2014. View Article : Google Scholar : PubMed/NCBI
7	Phan VK, Nguyen TM, Minh CV, Nguyen HK, Nguyen HD, Nguyen PT, Nguyen XC, Nguyen HN, Nguyen XN, Heyden YV, et al: Two new C-glucosyl benzoic acids and flavonoids from Mallotus nanus and their antioxidant activity. Arch Pharm Res. 33:203–208. 2010. View Article : Google Scholar : PubMed/NCBI
8	Yang H, Sung SH, Kim J and Kim YC: Neuroprotective diarylheptanoids from the leaves and twigs of juglans sinensis against glutamate-induced toxicity in HT22 cells. Planta Med. 77:841–845. 2011. View Article : Google Scholar
9	Kim HH, Oh MH, Park KJ, Heo JH and Lee MW: Anti-inflammatory activity of sulfate-containing phenolic compounds isolated from the leaves of Myrica rubra. Fitoterapia. 92:188–193. 2014. View Article : Google Scholar
10	Nguelefack TB, Mbakam FH, Tapondjou LA, Watcho P, Nguelefack-Mbuyo EP, Ponou BK, Kamanyi A and Park HJ: A dimeric triterpenoid glycoside and flavonoid glycosides with free radical-scavenging activity isolated from Rubus rigidus var. camerunensis. Arch Pharm Res. 34:543–550. 2011. View Article : Google Scholar : PubMed/NCBI
11	Schwarz S, Sauter D, Wang K, Zhang R, Sun B, Karioti A, Bilia AR, Efferth T and Schwarz W: Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Med. 80:177–182. 2014. View Article : Google Scholar : PubMed/NCBI
12	Asgari M, White E and Chren MM: Nonsteroidal anti-inflammatory drug use in the prevention and treatment of squamous cell carcinoma. Dermatol Surg. 30:1335–1342. 2004.PubMed/NCBI
13	Khan N, Syed DN, Pal HC, Mukhtar H and Afaq F: Pomegranate fruit extract inhibits UVB-induced inflammation and proliferation by modulating NF-κB and MAPK signaling pathways in mouse skin. Photochem Photobiol. 88:1126–1134. 2012. View Article : Google Scholar :
14	Thompson EJ, MacGowan J, Young MR, Colburn N and Bowden GT: A dominant negative c-jun specifically blocks okadaic acid-induced skin tumor promotion. Cancer Res. 62:3044–3047. 2002.PubMed/NCBI
15	Pal HC, Sharma S, Elmets CA, Athar M and Afaq F: Fisetin inhibits growth, induces G₂/M arrest and apoptosis of human epidermoid carcinoma A431 cells: role of mitochondrial membrane potential disruption and consequent caspases activation. Exp Dermatol. 22:470–4752. 2013. View Article : Google Scholar : PubMed/NCBI
16	Meek DW: Tumour suppression by p53: a role for the DNA damage response? Nat Rev Cancer. 9:714–723. 2009. View Article : Google Scholar : PubMed/NCBI
17	Zhang Q, Bian H, Li Y, Guo L, Tang Y and Zhu H: Preconditioning with the traditional Chinese medicine Huang-Lian-Jie-Du-Tang initiates HIF-1α-dependent neuroprotection against cerebral ischemia in rats. J Ethnopharmacol. 154:443–452. 2014. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
19	Pal HC, Athar M, Elmets CA and Afaq F: Fisetin inhibits UVB-induced cutaneous inflammation and activation of PI3K/AKT/NFκB signaling pathways in SKH-1 hairless mice. Photochem Photobiol. 91:225–234. 2015. View Article : Google Scholar
20	Afaq F, Adhami VM and Mukhtar H: Photochemoprevention of ultraviolet B signaling and photocarcinogenesis. Mutat Res. 571:153–173. 2005. View Article : Google Scholar : PubMed/NCBI
21	Bowden GT: Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signalling. Nat Rev Cancer. 4:23–35. 2004. View Article : Google Scholar
22	Segrelles C, Lu J, Hammann B, Santos M, Moral M, Cascallana JL, Lara MF, Rho O, Carbajal S, Traag J, et al: Deregulated activity of Akt in epithelial basal cells induces spontaneous tumors and heightened sensitivity to skin carcinogenesis. Cancer Res. 67:10879–10888. 2007. View Article : Google Scholar : PubMed/NCBI
23	Neagu M, Constantin C, Dumitrascu GR, Lupu AR, Caruntu C, Boda D and Zurac S: Inflammation markers in cutaneous melanoma - edgy biomarkers for prognosis. Discoveries. 3:e382015. View Article : Google Scholar
24	Fujiki H, Sueoka E and Suganuma M: Tumor promoters: from chemicals to inflammatory proteins. J Cancer Res Clin Oncol. 139:1603–1614. 2013. View Article : Google Scholar : PubMed/NCBI
25	Yan C, Grimm WA, Garner WL, Qin L, Travis T, Tan N and Han YP: Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol. 176:2247–2258. 2010. View Article : Google Scholar : PubMed/NCBI
26	Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB and Coldiron BM: Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 146:283–287. 2010. View Article : Google Scholar : PubMed/NCBI
27	Tak PP and Firestein GS: NF-kappaB: a key role in inflammatory diseases. J Clin Invest. 107:7–11. 2001. View Article : Google Scholar : PubMed/NCBI
28	Li J, Cheng Y, Qu W, Sun Y, Wang Z, Wang H and Tian B: Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol. 108:84–93. 2011. View Article : Google Scholar
29	Kassi E, Sourlingas TG, Spiliotaki M, Papoutsi Z, Pratsinis H, Aligiannis N and Moutsatsou P: Ursolic acid triggers apoptosis and Bcl-2 downregulation in MCF-7 breast cancer cells. Cancer Invest. 27:723–733. 2009. View Article : Google Scholar : PubMed/NCBI
30	Kornek T and Augustin M: Skin cancer prevention. J Dtsch Dermatol Ges. 11:283–296. 2013.PubMed/NCBI
31	Nijsten T, Colpaert CG, Vermeulen PB, Harris AL, Van Marck E and Lambert J: Cyclooxygenase-2 expression and angiogenesis in squamous cell carcinoma of the skin and its precursors: a paired immunohistochemical study of 35 cases. Br J Dermatol. 151:837–845. 2004. View Article : Google Scholar : PubMed/NCBI
32	Kim RH and Armstrong AW: Nonmelanoma skin cancer. Dermatol Clin. 30:125–139. 2012. View Article : Google Scholar
33	Li B, Zhang G, Li R and Duan C: Phosphoinositide 3-kinase/Akt Pathway Mediates Fip1-like1-platelet-derived Growth Factor Receptor α-induced Cell Infiltration and Activation: Possible Molecular Mechanism for the Malignant Phenotype of Chronic Eosinophilic Leukemia. Cancer Transl Med. 1:31–34. 2015. View Article : Google Scholar
34	George J, Singh M, Srivastava AK, Bhui K, Roy P, Chaturvedi PK and Shukla Y: Resveratrol and black tea polyphenol combination synergistically suppress mouse skin tumors growth by inhibition of activated MAPKs and p53. PLoS One. 6:e233952011. View Article : Google Scholar : PubMed/NCBI
35	Larisch P, Verwanger T, Linecker M and Krammer B: The interrelation between a pro-inflammatory milieu and fluorescence diagnosis or photodynamic therapy of human skin cell lines. Photodiagnosis Photodyn Ther. 11:91–103. 2014. View Article : Google Scholar : PubMed/NCBI
36	Joosse A, Koomen ER, Casparie MK, Herings RM, Guchelaar HJ and Nijsten T: Non-steroidal anti-inflammatory drugs and melanoma risk: large Dutch population-based case-control study. J Invest Dermatol. 129:2620–2627. 2009. View Article : Google Scholar : PubMed/NCBI
37	Johannesdottir SA, Chang ET, Mehnert F, Schmidt M, Olesen AB and Sørensen HT: Nonsteroidal anti-inflammatory drugs and the risk of skin cancer: a population-based case-control study. Cancer. 118:4768–4776. 2012. View Article : Google Scholar : PubMed/NCBI
38	Nedoszytko B, Sokołowska-Wojdyło M, Ruckemann-Dziurdzińska K, Roszkiewicz J and Nowicki RJ: Chemokines and cytokines network in the pathogenesis of the inflammatory skin diseases: atopic dermatitis, psoriasis and skin mastocytosis. Postepy Dermatol Alergol. 31:84–91. 2014. View Article : Google Scholar : PubMed/NCBI
39	Shen J, Abel EL, Riggs PK, Repass J, Hensley SC, Schroeder LJ, Temple A, Chau A, McClellan SA, Rho O, et al: Proteomic and pathway analyses reveal a network of inflammatory genes associated with differences in skin tumor promotion susceptibility in DBA/2 and C57BL/6 mice. Carcinogenesis. 33:2208–2219. 2012. View Article : Google Scholar : PubMed/NCBI
40	Suganuma M, Okabe S, Kurusu M, Iida N, Ohshima S, Saeki Y, Kishimoto T and Fujiki H: Discrete roles of cytokines, TNF-α IL-1, IL-6 in tumor promotion and cell transformation. Int J Oncol. 20:131–136. 2002.
41	Yang C, Zhao T, Lin M, Zhao Z, Hu L, Jia Y, Xue Y, Xu M, Tang Q, Yang B, et al: Helix B surface peptide administered after insult of ischemia reperfusion improved renal function, structure and apoptosis through beta common receptor/erythropoietin receptor and PI3K/Akt pathway in a murine model. Exp Biol Med (Maywood). 238:111–119. 2013. View Article : Google Scholar
42	Moore T, Beltran L, Carbajal S, Strom S, Traag J, Hursting SD and DiGiovanni J: Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. Cancer Prev Res (Phila). 1:65–76. 2008. View Article : Google Scholar
43	Wilker E, Lu J, Rho O, Carbajal S, Beltrá L and DiGiovanni J: Role of PI3K/Akt signaling in insulin-like growth factor-1 (IGF-1) skin tumor promotion. Mol Carcinog. 44:137–145. 2005. View Article : Google Scholar : PubMed/NCBI
44	Kleiner HE, Vulimiri SV, Starost MF, Reed MJ and DiGiovanni J: Oral administration of the citrus coumarin, isopimpinellin, blocks DNA adduct formation and skin tumor initiation by 7,12-dimethylbenz[a]anthracene in SENCAR mice. Carcinogenesis. 23:1667–1675. 2002. View Article : Google Scholar : PubMed/NCBI
45	Chen T: The role of microRNA in chemical carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 28:89–124. 2010. View Article : Google Scholar : PubMed/NCBI
46	Li J, Qu W, Cheng Y, Sun Y, Jiang Y, Zou T, Wang Z, Xu Y and Zhao H: The inhibitory effect of intravesical fisetin against bladder cancer by induction of p53 and down-regulation of NF-kappa B pathways in a rat bladder carcinogenesis model. Basic Clin Pharmacol Toxicol. 115:321–329. 2014. View Article : Google Scholar : PubMed/NCBI
47	Wong YK, Lin SC, Chang CS, Tseng YH, Liu CJ, Lin HC and Chang KW: Cyclin D1 genotype in areca-associated oral squamous cell carcinoma. J Oral Pathol Med. 32:265–270. 2003. View Article : Google Scholar : PubMed/NCBI
48	Yaylim-Eraltan I, Arikan S, Yildiz Y, Cacina C, Ergen HA, Tuna G, Görmüs U, Zeybek U and Isbir T: The influence of cyclin D1 A870G polymorphism on colorectal cancer risk and prognosis in a Turkish population. Anticancer Res. 30:2875–2880. 2010.PubMed/NCBI