Resveratrol induced reactive oxygen species and endoplasmic reticulum stress‑mediated apoptosis, and cell cycle arrest in the A375SM malignant melanoma cell line

Heo,Jae‑Rim; Kim,Soo‑Min; Hwang,Kyung‑A; Kang,Ji‑Houn; Choi,Kyung‑Chul

doi:10.3892/ijmm.2018.3732

Resveratrol induced reactive oxygen species and endoplasmic reticulum stress‑mediated apoptosis, and cell cycle arrest in the A375SM malignant melanoma cell line

Authors:
- Jae‑Rim Heo
- Soo‑Min Kim
- Kyung‑A Hwang
- Ji‑Houn Kang
- Kyung‑Chul Choi
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Affiliations: Laboratory of Biochemistry and Immunology, Veterinary Medical Center, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea, Laboratory of Internal Medicine, Veterinary Medical Center, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
Published online on: June 15, 2018 https://doi.org/10.3892/ijmm.2018.3732
Pages: 1427-1435
Copyright: © Heo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Resveratrol, a dietary product present in grapes, vegetables and berries, regulates several signaling pathways that control cell division, cell growth, apoptosis and metastasis. Malignant melanoma proliferates more readily in comparison with any other types of skin cancer. In the present study, the anti‑cancer effect of resveratrol on melanoma cell proliferation was evaluated. Treating A375SM cells with resveratrol resulted in a decrease in cell growth. The alteration in the levels of cell cycle‑associated proteins was also examined by western blot analysis. Treatment with resveratrol was observed to increase the gene expression levels of p21 and p27, as well as decrease the gene expression of cyclin B. In addition, the generation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress were confirmed at the cellular and protein levels using a 2',7'‑dichlorofluorescein diacetate assay, TUNEL assay and western blot analysis. Resveratrol induced the ROS‑p38‑p53 pathway by increasing the gene expression of phosphorylated p38 mitogen‑activated protein kinase, while it induced the p53 and ER stress pathway by increasing the gene expression levels of phosphorylated eukaryotic initiation factor 2α and C/EBP homologous protein. The enhanced ROS‑p38‑p53 and ER stress pathways promoted apoptosis by downregulating B‑cell lymphoma‑2 (Bcl‑2) expression and upregulating Bcl‑2‑associated X protein expression. In conclusion, resveratrol appears to be an inducer of ROS generation and ER stress, and may be responsible for growth inhibition and cell cycle arrest of A375SM melanoma cells.

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1	Bandarchi B, Ma L, Navab R, Seth A and Rasty G: From melanocyte to metastatic malignant melanoma. Dermatol Res Pract. 2010:2010. View Article : Google Scholar : PubMed/NCBI
2	Vogelstein B and Kinzler KW: The genetic evolution of melanoma. N Engl J Med. 374:9962016.PubMed/NCBI
3	Wellbrock C and Arozarena I: The complexity of the ERK/MAP-kinase pathway and the treatment of melanoma skin cancer. Front Cell Dev Biol. 4:332016. View Article : Google Scholar : PubMed/NCBI
4	Heo JR, Kim NH, Cho J and Choi KC: Current treatments for advanced melanoma and introduction of a promising novel gene therapy for melanoma (Review). Oncol Rep. 36:1779–1786. 2016. View Article : Google Scholar : PubMed/NCBI
5	Kraft TE, Parisotto D, Schempp C and Efferth T: Fighting cancer with red wine? Molecular mechanisms of resveratrol. Crit Rev Food Sci Nutr. 49:782–799. 2009. View Article : Google Scholar
6	Lee GA, Hwang KA and Choi KC: Roles of dietary phytoestrogens on the regulation of epithelial-mesenchymal transition in diverse cancer metastasis. Toxins (Basel). 8. pp. E1622016, View Article : Google Scholar
7	Marcsek ZL, Kocsis Z, Szende B and Tompa A: Effect of formaldehyde and resveratrol on the viability of Vero, HepG2 and MCF-7 cells. Cell Biol Int. 31:1214–1219. 2007. View Article : Google Scholar : PubMed/NCBI
8	Reagan-Shaw S, Mukhtar H and Ahmad N: Resveratrol imparts photoprotection of normal cells and enhances the efficacy of radiation therapy in cancer cells. Photochem Photobiol. 84:415–421. 2008. View Article : Google Scholar : PubMed/NCBI
9	Baarine M, Thandapilly SJ, Louis XL, Mazué F, Yu L, Delmas D, Netticadan T, Lizard G and Latruffe N: Pro-apoptotic versus anti-apoptotic properties of dietary resveratrol on tumoral and normal cardiac cells. Genes Nutr. 6:161–169. 2011. View Article : Google Scholar : PubMed/NCBI
10	Athar M, Back JH, Kopelovich L, Bickers DR and Kim AL: Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms. Arch Biochem Biophys. 486:95–102. 2009. View Article : Google Scholar : PubMed/NCBI
11	Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, et al: Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 275:218–220. 1997. View Article : Google Scholar : PubMed/NCBI
12	Rojas C, Pan-Castillo B, Valls C, Pujadas G, Garcia-Vallve S, Arola L and Mulero M: Resveratrol enhances palmitate-induced ER stress and apoptosis in cancer cells. PLoS One. 9:e1139292014. View Article : Google Scholar : PubMed/NCBI
13	Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP and Ron D: CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18:3066–3077. 2004. View Article : Google Scholar : PubMed/NCBI
14	Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl JA and Majsterek I: The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr Mol Med. 16:533–544. 2016. View Article : Google Scholar
15	Yen YP, Tsai KS, Chen YW, Huang CF, Yang RS and Liu SH: Arsenic induces apoptosis in myoblasts through a reactive oxygen species-induced endoplasmic reticulum stress and mitochondrial dysfunction pathway. Arch Toxicol. 86:923–933. 2012. View Article : Google Scholar : PubMed/NCBI
16	Birben E, Sahiner UM, Sackesen C, Erzurum S and Kalayci O: Oxidative stress and antioxidant defense. World Allergy Organ J. 5:9–19. 2012. View Article : Google Scholar : PubMed/NCBI
17	Poljsak B, Šuput D and Milisav I: Achieving the balance between ROS and antioxidants: When to use the synthetic antioxidants. Oxid Med Cell Longev. 2013:9567922013. View Article : Google Scholar : PubMed/NCBI
18	Sies H: Oxidative stress: From basic research to clinical application. Am J Med. 91:31S–38S. 1991. View Article : Google Scholar : PubMed/NCBI
19	Zhou Y, Wang K, Zhen S, Wang R and Luo W: Carfilzomib induces G2/M cell cycle arrest in human endometrial cancer cells via upregulation of p21(Waf1/Cip1) and p27Kip1. Taiwan J Obstet Gynecol. 55:847–851. 2016. View Article : Google Scholar
20	Tyner AL: A new year, a new role for p21. Cell Cycle. 8:1832009. View Article : Google Scholar : PubMed/NCBI
21	Vaseva AV and Moll UM: The mitochondrial p53 pathway. Biochim Biophys Acta. 1787:414–420. 2009. View Article : Google Scholar
22	Maverakis E, Cornelius LA, Bowen GM, Phan T, Patel FB, Fitzmaurice S, He Y, Burrall B, Duong C, Kloxin AM, et al: Metastatic melanoma-a review of current and future treatment options. Acta Derm Venereol. 95:516–524. 2015. View Article : Google Scholar
23	Shukla Y and Singh R: Resveratrol and cellular mechanisms of cancer prevention. Ann NY Acad Sci. 1215:1–8. 2011. View Article : Google Scholar : PubMed/NCBI
24	Georgieva J, Sinha P and Schadendorf D: Expression of cyclins and cyclin dependent kinases in human benign and malignant melanocytic lesions. J Clin Pathol. 54:229–235. 2001. View Article : Google Scholar : PubMed/NCBI
25	Heiss EH, Schilder YD and Dirsch VM: Chronic treatment with resveratrol induces redox stress- and ataxia telangiectasia-mutated (ATM)-dependent senescence in p53-positive cancer cells. J Biol Chem. 282:26759–26766. 2007. View Article : Google Scholar : PubMed/NCBI
26	de la Lastra CA and Villegas I: Resveratrol as an antioxidant and pro-oxidant agent: Mechanisms and clinical implications. Biochem Soc Trans. 35:1156–1160. 2007. View Article : Google Scholar : PubMed/NCBI
27	Singh A, Sati S and Mishra R: Resveratrol: Antioxidant-pro-oxidant. In J Tech Res Sci. 1:106–112. 2016.
28	Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, Chen W, Yi X, Zheng W, Wondrak GT, et al: Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 29:1235–1243. 2008. View Article : Google Scholar : PubMed/NCBI
29	Menegon S, Columbano A and Giordano S: The dual roles of NRF2 in cancer. Trends Mol Med. 22:578–593. 2016. View Article : Google Scholar : PubMed/NCBI
30	Hayes JD, McMahon M, Chowdhry S and Dinkova-Kostova AT: Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal. 13:1713–1748. 2010. View Article : Google Scholar : PubMed/NCBI
31	Rachakonda G, Sekhar KR, Jowhar D, Samson PC, Wikswo JP, Beauchamp RD, Datta PK and Freeman ML: Increased cell migration and plasticity in Nrf2-deficient cancer cell lines. Oncogene. 29:3703–3714. 2010. View Article : Google Scholar : PubMed/NCBI
32	Ma Q: Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 53:401–426. 2013. View Article : Google Scholar : PubMed/NCBI
33	Moon EJ and Giaccia A: Dual roles of NRF2 in tumor prevention and progression: Possible implications in cancer treatment. Free Radic Biol Med. 79:292–299. 2015. View Article : Google Scholar
34	Lau A, Villeneuve NF, Sun Z, Wong PK and Zhang DD: Dual roles of Nrf2 in cancer. Pharmacol Res. 58:262–270. 2008. View Article : Google Scholar : PubMed/NCBI
35	Sood R, Porter AC, Ma K, Quilliam LA and Wek RC: Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. Biochem J. 346:281–293. 2000. View Article : Google Scholar : PubMed/NCBI
36	Xu C, Bailly-Maitre B and Reed JC: Endoplasmic reticulum stress: Cell life and death decisions. J Clin Invest. 115:2656–2664. 2005. View Article : Google Scholar : PubMed/NCBI
37	Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L and Wek RC: Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol. 18:7499–7509. 1998. View Article : Google Scholar : PubMed/NCBI
38	Liu B, Cheng Y, Zhang B, Bian HJ and Bao JK: Polygonatum cyrtonem lectin induces apoptosis and autophagy in human melanoma A375 cells through a mitochondria-mediated ROS-p38-p53 pathway. Cancer Lett. 275:54–60. 2009. View Article : Google Scholar