Gossypetin Inhibits Solar-UV Induced Cutaneous Basal Cell Carcinoma Through Direct Inhibiting PBK/TOPK Protein Kinase

Author(s): Lijuan Wang , Zixi Zhang , Rui Ge , Jian Zhang , Wenli Liu , Kuanhou Mou , Shemin Lv , Xin Mu* .

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 19 , Issue 8 , 2019

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Graphical Abstract:


Abstract:

Background: Skin photoaging, skin inflammation and skin cancer are related with excessive exposure to solar UV. PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK), a member of the serine/threonine protein kinase, which regulates the signaling cascades of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal regulated kinase 1/2 (ERK1/2). PBK/TOPK plays a significant role in solar-UV-induced cutaneous basal cell carcinoma (BCC), and targeting PBK/TOPK can be supposed to treat and prevent cutaneous BCC.

Methods: The pathological feature and the expression level of PBK/TOPK in cutaneous BCC tissues of human were studied in clinical samples. SUV-induced the phosphorylation of p38 MAPK and ERK1/2 were demonstrated ex vivo. Moreover, the interaction between Gossypetin and PBK/TOPK were detected by in vitro kinase assay and Microscale thermophoresis (MST) assay. Furthermore, the effect of Gossypetin to solar UV-induced the activity of PBK/TOPK were detected ex vivo and in vivo.

Results: The clinical samples showed that the expression levels of PBK/TOPK, phosphor-p38 MAPK and phosphor- ERK1/2 were up-regulated in cutaneous BCC tissues of human. The expression of phosphor-p38 MAPK or phosphor-ERK1/2 increased in a dose and time dependent manner after solar UV treatment in HaCaT cells. MTT cytotoxicity assay results showed that Gossypetin has no effect on HaCaT cells. In vitro kinase assay and MST assay results showed that Gossypetin bound with PBK/TOPK and suppressed PBK/TOPK activity. Ex vivo results showed Gossypetin inhibited solar UV-induced phosphorylation of PBK/TOPK, p38 MAPK, ERK1/2 and H2AX by suppressing PBK/TOPK activity. In vivo test results indicated that Gossypetin suppressed solar UV-induced increase of PBK/TOPK, phosphor-p38 MAPK, phosphor-ERK1/2 and phosphor- H2AX in SKH-1 hairless mice.

Conclusion: Our data demonstrated that Gossypetin can alleviate solar-UV-induced cutaneous BCC by blocking PBK/TOPK, and Gossypetin could be a remarkable agent for treating solar-UV induced cutaneous basal cell carcinoma.

Keywords: Gossypetin, PBK/TOPK, solar-UV, cutaneous basal cell carcinoma, MAPK, microscale thermophoresis assay.

[1]
Ren, X.; Shi, Y.; Zhao, D.; Xu, M.; Li, X.; Dang, Y.; Ye, X. Naringin protects ultraviolet B-induced skin damage by regulating p38 MAPK signal pathway. J. Dermatol. Sci., 2016, 82(2), 106-114.
[2]
de Gruijl, F.R.; van-der-Leun, J.C. Environment and health: Ozone depletion and ultraviolet radiation. CMAJ, 2000, 163(7), 851-855.
[3]
Svobodova, A.; Walterova, D.; Vostalova, J. Ultraviolet might induce alteration to the skin. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub., 2006, 150(1), 25-38.
[4]
Nicolaoua, A.; Pilkingtonb, S.M.; Rhodes, L.E. Ultraviolet-radiation induced skin inflammation: Dissecting the role of bioactive lipids. Chem. Phys. Lipids, 2011, 164(3), 535-543.
[5]
Ichihashi, M.; Ueda, M.; Budiyanto, A.; Bito, T.; Oka, M.; Fukunaga, M.; Tsuru, K. Horikawa, T. UV-induced skin damage. Toxicology, 2003, 189(1-2), 21-39.
[6]
Abe, Y.; Matsumoto, S.; Kito, K.; Ueda, N. Cloning and expression of a novel MAPKK-like protein kinase, lymphokine-activated killer T-cell-originated protein kinase, specifically expressed in the testis and activated lymphoid cells. J. Biol. Chem., 2000, 275(28), 21525-21531.
[7]
Abe, Y.; Matsumoto, S.; Kito, K.; Ueda, N. Cloning and expression of a novel MAPKK-like protein kinase, lymphokine-activated killer T-cell-originated protein kinase, specifcally expressed in the testis and activated lymphoid cells. J. Biol. Chem., 2000, 275, 21525-21531.
[8]
Zhu, F.; Zykova, T.A.; Kang, B.S.; Wang, Z.; Ebeling, M.C.; Abe, Y.; Ma, W.Y.; Bode, A.M.; Dong, Z. Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells. Gastroenterology, 2007, 133(1), 219-231.
[9]
Fan, X.; Duan, Q.; Ke, C.; Zhang, G.; Xiao, J.; Wu, D.; Zeng, X.; Chen, J.; Guo, J.; Zhou, J.; Shi, F.; Zhu, F. Cefradine blocks solar-ultraviolet induced skin inflammation through direct inhibition of T-LAK cell-originated protein kinase. Oncotarget, 2016, 7(17), 24633-24645.
[10]
Zykova, T.A.; Zhu, F.; Vakorina, T.I.; Zhang, J.; Higgins, L.A.; Urusova, D.V.; Bode, A.M.; Dong, Z.T-L.A.K. Cell-originated Protein Kinase (TOPK) phosphorylation of prx1 at ser-32 prevents UVB-induced apoptosis in RPMI7951 melanoma cells through the regulation of prx1 peroxidase activity. J. Biol. Chem., 2010, 285, 29138-29146.
[11]
Zeng, X.; Liu, L.; Zheng, M.; Sun, H.; Xiao, J.; Lu, T.; Huang, G.; Chen, P.; Zhang, J.; Zhu, F.; Li, H.; Duan, Q. Pantoprazole, an FDA-approved proton-pump inhibitor, suppresses colorectal cancer growth by targeting T-cell-originated protein kinase. Oncotarget, 2016, 7(16), 22460-22473.
[12]
Park, J.H.; Inoue, H.; Kato, T.; Zewde, M.; Miyamoto, T.; Matsuo, Y.; Salgia, R.; Nakamura, Y. TOPK (T-LAK cell-originated protein kinase) inhibitor exhibits growth suppressive effect on small cell lung cancer. Cancer Sci., 2017, 108(3), 488-496.
[13]
Fukukawa, C.; Ueda, K.; Nishidate, T.; Katagiri, T.; Nakamura, Y. Critical roles of LGN/GPSM2 phosphorylation by PBK/TOPK in cell division of breast cancer cells. Genes Chromosomes Cancer, 2010, 49(10), 861-872.
[14]
Joel, M.; Mughal, A.A.; Grieg, Z.; Murrell, W.; Palmero, S.; Mikkelsen, B.; Fjerdingstad, H.B.; Sandberg, C.J.; Behnan, J.; Glover, J.C.; Langmoen, I.A.; Stangeland, B. Targeting PBK/TOPK decreases growth and survival of glioma initiating cells in vitro and attenuates tumor growth in vivo. Mol. Cancer, 2015, 17(14), 121.
[15]
Chen, F.; Li, R.; Wang, C.; Cao, L.; Wang, Y.; Yu, L. T-LAK cell-originated protein kinase is essential for the proliferation of hepatocellular carcinoma SMMC-7721 cells. Cell Biochem. Funct., 2013, 31(8), 736-742.
[16]
Khan, A.; Manna, K.; Bose, C.; Sinha, M.; Das, D.K.; Kesh, S.B.; Chakrabarty, A.; Banerji, A.; Dey, S. Gossypetin, a naturally occurring hexahydroxy flavone, ameliorates gamma radiation-mediated DNA damage. Int. J. Radiat. Biol., 2013, 89(11), 965-975.
[17]
Khan, A.; Manna, K.; Das, D.K.; Kesh, S.B.; Sinha, M.; Das, U.; Biswas, S.; Sengupta, A.; Sikder, K.; Datta, S.; Ghosh, M.; Chakrabarty, A.; Banerji, A.; Dey, S. Gossypetin ameliorates ionizing radiation-induced oxidative stress in mice liver--a molecular approach. Free Radic. Res., 2015, 49(10), 1173-1186.
[18]
Chen, J.H.; Tsai, C.W.; Wang, C.P.; Lin, H.H. Anti-atherosclerotic potential of gossypetin via inhibiting LDL oxidation and foam cell formation. Appl. Pharmacol., 2013, 272(2), 313-324.
[19]
Lin, H.H. in vitro and in vivo atheroprotective effects of gossypetin against endothelial cell injury by induction of autophagy. Chem. Res. Toxicol., 2015, 28(2), 202-215.
[20]
Miceli, N.; Trovato, A.; Dugo, P.; Cacciola, F.; Donato, P.; Marino, A.; Bellinghieri, V.; La-Barbera, T.M.; Güvenç, A.; Taviano, M.F. Comparative analysis of flavonoid profile, antioxidant and antimicrobial activity of the berries of Juniperus communis L. var. communis and Juniperus communis L. var. saxatilis Pall. from Turkey. J. Agric. Food Chem., 2009, 57(15), 6570-6577.
[21]
Babu, B.H.; Jayram, H.N.; Nair, M.G.; Ajaikumar, K.B.; Padikkala, J. Free radical scavenging, antitumor and anticarcinogenic activity of gossypin. J. Exp. Clin. Cancer Res., 2003, 22(4), 581-589.
[22]
Bhaskaran, S.; Dileep, K.V.; Deepa, S.S.; Sadasivan, C.; Klausner, M.; Krishnegowda, N.K.; Tekmal, R.R.; VandeBerg, J.L.; Nair, H.B. Gossypin as a novel selective dual inhibitor of V-RAF murine sarcoma viral oncogene homolog B1 and cyclin-dependent kinase 4 for melanoma. Mol. Cancer Ther., 2013, 12(4), 361-372.
[23]
Pacholczyk, M.; Czernicki, J.; Ferenc, T. The effect of solar ultraviolet radiation (UVR) on induction of skin cancers. Med. Pr., 2016, 67(2), 255-266.
[24]
Liu, K.; Yu, D.; Cho, Y.Y.; Bode, A.M.; Ma, W.; Yao, K.; Li, S.; Li, J.; Bowden, G.T.; Dong, Z.; Dong, Z. Sunlight UV-induced skin cancer relies upon activation of the p38α signaling pathway. Cancer Res., 2013, 73(7), 2181-2188.
[25]
Yang, G.; Fu, Y.; Malakhova, M.; Kurinov, I.; Zhu, F.; Yao, K.; Li, H.; Chen, H.; Li, W.; Lim, D.Y.; Sheng, Y.; Bode, A.M.; Dong, Z.; Dong, Z. Caffeic acid directly targets ERK1/2 to attenuate solar-UV-induced skin carcinogenesis. Cancer Prev. Res. (Phila.), 2014, 7(10), 1056-1066.
[26]
Ahmad, I.; Muneer, K.M.; Chang, M.E.; Nasr, H.M.; Clay, J.M.; Huang, C.C.; Yusuf, N. Ultraviolet radiation-induced downregulation of SERCA2 mediates activation of NLRP3 inflammasome in basal cell carcinoma. Photochem. Photobiol., 2017, 93(4), 1025-1033.
[27]
Chen, C.Y.; Chen, C.J.; Lai, C.H.; Wu, B.Y.; Lee, S.P.; Johnson, M.D.; Lin, C.Y.; Wang, J.K. Increased matriptase zymogen activation by UV irradiation protects keratinocyte from cell death. J. Dermatol. Sci., 2016, 83(1), 34-44.
[28]
Wienken, C.J.; Baaske, P.; Rothbauer, U.; Braun, D.; Duhr, S. Protein-binding assays in biological liquids using microscale thermophoresis. Nat. Commun., 2010, 19(1), 100.
[29]
Kuo, L.J.; Yang, L.X. Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo, 2008, 22(3), 305-309.
[30]
Zykova, T.A.; Zhu, F.; Lu, C.; Higgins, L.; Tatsumi, Y.; Abe, Y.; Bode, A.M.; Dong, Z. Lymphokine-activated killer T-celloriginated protein kinase phosphorylation of histone H2AX prevents arsenite-induced apoptosis in RPMI7951 melanoma cells. Clin. Cancer Res., 2006, 12(23), 6884-6893.
[31]
Kim, D.J.; Li, Y.; Reddy, K.; Lee, M.H.; Kim, M.O.; Cho, Y.Y.; Lee, S.Y.; Kim, J.E.; Bode, A.M.; Dong, Z. Novel TOPK inhibitor HI-TOPK-032 effectively suppresses colon cancer growth. Cancer Res., 2012, 72(12), 3060-3068.
[32]
Mo, Q.; Zhang, Y.; Jin, X.; Gao, Y.; Wu, Y.; Hao, X.; Gao, Q.; Chen, P. Geldanamycin, an inhibitor of Hsp90, increases paclitaxel-mediated toxicity in ovarian cancer cells through sustained activation of the p38/H2AX axis. Tumour Biol., 2016, 37(11), 14745-14755.
[33]
Katiyar, S.K.; Matsui, M.S.; Mukhtar, H. Kinetics of UV light-induced cyclobutane pyrimidine dimers in human skin in vivo: an immunohistochemical analysis of both epidermis and dermis. Photochem. Photobiol., 2000, 72(6), 788-793.
[34]
Cadet, J.; Sage, E.; Douki, T. Ultraviolet radiation-mediated damage to cellular DNA. Mutat. Res., 2005, 571(1-2), 3-17.
[35]
Kammeyer, A.; Luiten, R.M. Oxidation events and skin aging. Ageing Res. Rev., 2015, 21, 16-29.
[36]
Ayllón, V.; O’connor, R. PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response. Oncogene, 2007, 26(24), 3451-3461.
[37]
Senft, C.; Polacin, M.; Priester, M.; Seifert, V.; Kögel, D.; Weissenberger, J. 2010 The nontoxic natural compound Curcumin exerts anti-proliferative, anti-migratory, and anti-invasive properties against malignant gliomas. BMC Cancer, 10, 491.
[38]
Gheorgheosu, D.; Duicu, O.; Dehelean, C.; Soica, C.; Muntean, D. Betulinic acid as a potent and complex antitumor phytochemical: A minireview. Anticancer. Agents Med. Chem., 2014, 14, 936-945.
[39]
Lin, H.H.; Chen, J.H.; Wang, C.J. Chemopreventive properties and molecular mechanisms of the bioactive compounds in Hibiscus sabdariffa Linne. Curr. Med. Chem., 2011, 18(8), 1245-1254.
[40]
Khan, A.; Manna, K.; Bose, C.; Sinha, M.; Das, D.K.; Kesh, S.B.; Chakrabarty, A.; Banerji, A.; Dey, S. Gossypetin, a naturally occurring hexahydroxy flavone, ameliorates gamma radiation-mediated DNA damage. Int. J. Radiat. Biol., 2013, 89(11), 965-975.
[41]
Pan, H.; Zhou, W.; He, W.; Liu, X.; Ding, Q.; Ling, L.; Zha, X.; Wang, S. Genistein inhibits MDA-MB-231 triple-negative breast cancer cell growth by inhibiting NF-κB activity via the Notch-1 pathway. Int. J. Mol. Med., 2012, 30(2), 337-343.
[42]
Li, F.; Wang, Y.; Wang, X.; Li, J.; Cui, H.; Niu, M. Ganoderic acids suppress growth and angiogenesis by modulating the NF-κB signaling pathway in breast cancer cells. Int. J. Clin. Pharmacol. Ther., 2012, 50(10), 712-721.
[43]
Chen, L.F.; Fischle, W.; Verdin, E.; Greene, W.C. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science, 2001, 293(5535), 1653-1657.
[44]
Zhang, X.; Luo, S.; Wu, J.; Zhang, L.; Wang, W.H.; Degan, S.; Erdmann, D.; Hall, R.; Zhang, J.Y. KIND1 loss sensitizes keratinocytes to UV-induced inflammatory response and DNA damage. J. Invest. Dermatol., 2017, 137(2), 475-483.


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Article Details

VOLUME: 19
ISSUE: 8
Year: 2019
Page: [1029 - 1036]
Pages: 8
DOI: 10.2174/1871520619666190301123131
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