Melatonin induces cell apoptosis in Mia PaCa-2 cells via the suppression of nuclear factor-κB and activation of ERK and JNK: A novel therapeutic implication for pancreatic cancer

Li,Weimin; Wu,Jiansheng; Li,Zhiyin; Zhou,Zhibo; Zheng,Chao; Lin,Le; Tan,Binbin; Huang,Min; Fan,Mengdi

doi:10.3892/or.2016.5100

Melatonin induces cell apoptosis in Mia PaCa-2 cells via the suppression of nuclear factor-κB and activation of ERK and JNK: A novel therapeutic implication for pancreatic cancer

Authors:
- Weimin Li
- Jiansheng Wu
- Zhiyin Li
- Zhibo Zhou
- Chao Zheng
- Le Lin
- Binbin Tan
- Min Huang
- Mengdi Fan
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Affiliations: Department of Gastroenterology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China, Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Infection, ZheJiang University International Hospital, Hangzhou, Zhejiang 310000, P.R. China, Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Gastroenterology, Taizhou Municipal Hospital, Taizhou, Zhejiang 318000, P.R. China, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Endocrinology, Zhejiang University International Hospital, Hangzhou, Zhejiang 310000, P.R. China
Published online on: September 16, 2016 https://doi.org/10.3892/or.2016.5100
Pages: 2861-2867

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Abstract

Melatonin is synthesized by the pineal gland and is released into the blood. In the last several years, some studies have shown that melatonin has anticancer properties; however, the mechanisms behind the antitumour traits are unclear, especially in pancreatic cancer. Therefore, in the present study, we investigated the antitumour effects of melatonin on the human pancreatic carcinoma cell line MIA PaCa‑2 and explored its biological mechanisms. MIA PaCa‑2 cells were treated with melatonin, and we used a CCK‑8 assay to evaluate the cell viability. We also used flow cytometry to observe cell apoptosis and western blot analysis to assess the protein expression. Our study found that melatonin inhibited cell viability, suppressed colony formation and reduced cell migration and invasion and induced cell apoptosis in MIA PaCa‑2 cells. Our results showed that melatonin treatment inhibited NF‑κB p65 activation. Moreover, melatonin treatment activated the mitogen‑activated protein kinase pathways (c‑jun N‑terminal kinase and extracellular‑regulated kinase 1/2), which increased Bax protein expression and caspase‑3 cleavage and decreased Bcl‑2 protein expression. These new developments demonstrate that melatonin plays a potential role in anticancer treatment and may act as an effective therapeutic agent in the future.

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1	Raimondi S, Maisonneuve P and Lowenfels AB: Epidemiology of pancreatic cancer: An overview. Nat Rev Gastroenterol Hepatol. 6:699–708. 2009. View Article : Google Scholar : PubMed/NCBI
2	Guo L, Fan L, Pang Z, Ren J, Ren Y, Li J, Chen J, Wen Z and Jiang X: TRAIL and doxorubicin combination enhances anti-glioblastoma effect based on passive tumor targeting of liposomes. J Control Release. 154:93–102. 2011. View Article : Google Scholar : PubMed/NCBI
3	Peixoto RD, Ho M, Renouf DJ, Lim HJ, Gill S, Ruan JY and Cheung WY: Eligibility of metastatic pancreatic cancer patients for first-line palliative intent nab-paclitaxel plus gemcitabine versus FOLFIRINOX. Am J Clin Oncol. 12015. View Article : Google Scholar
4	Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, et al: Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 364:1817–1825. 2011. View Article : Google Scholar : PubMed/NCBI
5	Lerner AB, Case JD, Takahashi Y, Lee TH and Mori W: Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc. 80:2587. 1958. View Article : Google Scholar
6	Berra B and Rizzo AM: Melatonin: Circadian rhythm regulator, chronobiotic, antioxidant and beyond. Clin Dermatol. 27:202–209. 2009. View Article : Google Scholar : PubMed/NCBI
7	Cardinali DP, Esquifino AI, Srinivasan V and Pandi- Perumal SR: Melatonin and the immune system in aging. Neuroimmunomodulation. 15:272–278. 2008. View Article : Google Scholar : PubMed/NCBI
8	Ambriz-Tututi M, Rocha-González HI, Cruz SL and Granados-Soto V: Melatonin: A hormone that modulates pain. Life Sci. 84:489–498. 2009. View Article : Google Scholar : PubMed/NCBI
9	Fischer TW, Kleszczyński K, Hardkop LH, Kruse N and Zillikens D: Melatonin enhances antioxidative enzyme gene expression (CAT, GPx, SOD), prevents their UVR-induced depletion, and protects against the formation of DNA damage (8-hydroxy-2′-deoxyguanosine) in ex vivo human skin. J Pineal Res. 54:303–312. 2013. View Article : Google Scholar
10	Shiu SY, Li L, Xu JN, Pang CS, Wong JT and Pang SF: Melatonin-induced inhibition of proliferation and G1/S cell cycle transition delay of human choriocarcinoma JAr cells: Possible involvement of MT2 (MEL1B) receptor. J Pineal Res. 27:183–192. 1999. View Article : Google Scholar : PubMed/NCBI
11	Xu L, Liu H, Zhang H, Wang RX, Song J and Zhou RX: Growth-inhibitory activity of melatonin on murine foregastric carcinoma cells in vitro and the underlying molecular mechanism. Anat Rec (Hoboken). 296:914–920. 2013. View Article : Google Scholar
12	Xu L, Jin QD, Gong X, Liu H and Zhou RX: Anti-gastric cancer effect of melatonin and Bcl-2, Bax, p21 and p53 expression changes. Sheng Li Xue Bao. 66:723–729. 2014.In Chinese. PubMed/NCBI
13	Ordoñez R, Carbajo-Pescador S, Prieto-Dominguez N, García-Palomo A, González-Gallego J and Mauriz JL: Inhibition of matrix metalloproteinase-9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells. J Pineal Res. 56:20–30. 2014. View Article : Google Scholar
14	Martín-Renedo J, Mauriz JL, Jorquera F, Ruiz-Andrés O, González P and González-Gallego J: Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. J Pineal Res. 45:532–540. 2008. View Article : Google Scholar : PubMed/NCBI
15	Vijayalaxmi, Reiter RJ, Tan DX, Herman TS and Thomas CR Jr: Melatonin as a radioprotective agent: A review. Int J Radiat Oncol Biol Phys. 59:639–653. 2004. View Article : Google Scholar : PubMed/NCBI
16	Chang L and Karin M: Mammalian MAP kinase signalling cascades. Nature. 410:37–40. 2001. View Article : Google Scholar : PubMed/NCBI
17	Hsieh MH and Nguyen HT: Molecular mechanism of apoptosis induced by mechanical forces. Int Rev Cytol. 245:45–90. 2005. View Article : Google Scholar : PubMed/NCBI
18	Joo SS and Yoo YM: Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: Therapeutic implications for prostate cancer. J Pineal Res. 47:8–14. 2009. View Article : Google Scholar : PubMed/NCBI
19	Crawford LJ, Walker B and Irvine AE: Proteasome inhibitors in cancer therapy. J Cell Commun Signal. 5:101–110. 2011. View Article : Google Scholar : PubMed/NCBI
20	Tamura EK, Cecon E, Monteiro AWA, Silva CLM and Markus RP: Melatonin inhibits LPS-induced NO production in rat endothelial cells. J Pineal Res. 46:268–274. 2009. View Article : Google Scholar : PubMed/NCBI
21	Gilad E, Wong HR, Zingarelli B, Virág L, O'Connor M, Salzman AL and Szabó C: Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: Role of inhibition of NFkappaB activation. FASEB J. 12:685–693. 1998.PubMed/NCBI
22	Hidalgo M, Cascinu S, Kleeff J, Labianca R, Löhr JM, Neoptolemos J, Real FX, Van Laethem JL and Heinemann V: Addressing the challenges of pancreatic cancer: Future directions for improving outcomes. Pancreatology. 15:8–18. 2015. View Article : Google Scholar
23	Xu B, Zhang K and Huang Y: Lin28 modulates cell growth and associates with a subset of cell cycle regulator mRNAs in mouse embryonic stem cells. RNA. 15:357–361. 2009. View Article : Google Scholar : PubMed/NCBI
24	Hsiang C-H, Tunoda T, Whang YE, Tyson DR and Ornstein DK: The impact of altered annexin I protein levels on apoptosis and signal transduction pathways in prostate cancer cells. Prostate. 66:1413–1424. 2006. View Article : Google Scholar : PubMed/NCBI
25	Mukherjee JJ, Gupta SK, Sikka H and Kumar S: Inhibition of benzopyrene-diol-epoxide (BPDE)-induced bax and caspase-9 by cadmium: Role of mitogen activated protein kinase. Mutat Res. 661:41–46. 2009. View Article : Google Scholar
26	Sainz RM, Reiter RJ, Tan DX, Roldan F, Natarajan M, Quiros I, Hevia D, Rodriguez C and Mayo JC: Critical role of glutathione in melatonin enhancement of tumor necrosis factor and ionizing radiation-induced apoptosis in prostate cancer cells in vitro. J Pineal Res. 45:258–270. 2008. View Article : Google Scholar : PubMed/NCBI
27	Huang HL, Hsieh MJ, Chien MH, Chen HY, Yang SF and Hsiao PC: Glabridin mediate caspases activation and induces apoptosis through JNK1/2 and p38 MAPK pathway in human promyelocytic leukemia cells. PLoS One. 9:e989432014. View Article : Google Scholar : PubMed/NCBI
28	Zhou Y, Zhao W, Xie G, Huang M, Hu M, Jiang X, Zeng D, Liu J, Zhou H, Chen H, et al: Induction of Nur77-dependent apoptotic pathway by a coumarin derivative through activation of JNK and p38 MAPK. Carcinogenesis. 35:2660–2669. 2014. View Article : Google Scholar : PubMed/NCBI
29	Liu J, Wu N, Ma L-N, Zhong JT, Liu G, Zheng LH and Lin XK: p38 MAPK signaling mediates mitochondrial apoptosis in cancer cells induced by oleanolic acid. Asian Pac J Cancer Prev. 15:4519–4525. 2014. View Article : Google Scholar : PubMed/NCBI
30	Aggarwal BB: Nuclear factor-kappaB: The enemy within. Cancer Cell. 6:203–208. 2004. View Article : Google Scholar : PubMed/NCBI
31	Deorukhkar A, Krishnan S, Sethi G and Aggarwal BB: Back to basics: How natural products can provide the basis for new therapeutics. Expert Opin Investig Drugs. 16:1753–1773. 2007. View Article : Google Scholar : PubMed/NCBI
32	Ahn KS and Aggarwal BB: Transcription factor NF-kappaB: A sensor for smoke and stress signals. Ann NY Acad Sci. 1056:218–233. 2005. View Article : Google Scholar
33	Yuan L, Wei S, Wang J and Liu X: Isoorientin induces apoptosis and autophagy simultaneously by reactive oxygen species (ROS)-related p53, PI3K/Akt, JNK, and p38 signaling pathways in HepG2 cancer cells. J Agric Food Chem. 62:5390–5400. 2014. View Article : Google Scholar : PubMed/NCBI
34	Bharti AC, Donato N, Singh S and Aggarwal BB: Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-κB and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood. 101:1053–1062. 2003. View Article : Google Scholar
35	Takada Y and Aggarwal BB: Flavopiridol inhibits NF-kappaB activation induced by various carcinogens and inflammatory agents through inhibition of IkappaBalpha kinase and p65 phosphorylation: Abrogation of cyclin D1, cyclooxygenase-2, and matrix metalloprotease-9. J Biol Chem. 279:4750–4759. 2004. View Article : Google Scholar
36	Rondanelli M, Faliva MA, Perna S and Antoniello N: Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep-wake and mood disturbances: Review and remarks. Aging Clin Exp Res. 25:499–510. 2013. View Article : Google Scholar : PubMed/NCBI