Reduction in MnSOD promotes the migration and invasion of squamous carcinoma cells

Fan,Jhen‑Jia; Hsu,Wen‑Hsien; Hung,Hao‑Hsiang; Zhang,Wei‑Jun; Lee,Yu‑Lin A; Chen,Ku‑Chung; Chu,Cheng‑Ying; Ko,Tzu‑Ping; Lee,Ming‑Ting; Lin,Cheng‑Wei; Cheng,Chia‑Hsiung

doi:10.3892/ijo.2019.4750

Reduction in MnSOD promotes the migration and invasion of squamous carcinoma cells

Authors:
- Jhen‑Jia Fan
- Wen‑Hsien Hsu
- Hao‑Hsiang Hung
- Wei‑Jun Zhang
- Yu‑Lin A Lee
- Ku‑Chung Chen
- Cheng‑Ying Chu
- Tzu‑Ping Ko
- Ming‑Ting Lee
- Cheng‑Wei Lin
- Chia‑Hsiung Cheng
View Affiliations

Affiliations: Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan, R.O.C., Department of Surgery, Wan‑Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Departments of Medicine and Pediatrics, Hospice and Palliative Medicine, Duke University Hospital, Durham, NC 27710, USA, Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan, R.O.C.
Published online on: March 14, 2019 https://doi.org/10.3892/ijo.2019.4750
Pages: 1639-1650
Copyright: © Fan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Reactive oxygen species (ROS) homeostasis is maintained at a higher level in cancer cells, which promotes tumorigenesis. Oxidative stress induced by anticancer drugs may further increase ROS to promote apoptosis, but can also enhance the metastasis of cancer cells. The effects of ROS homeostasis on cancer cells remain to be fully elucidated. In the present study, the effect of a reduction in manganese superoxide dismutase (MnSOD) on the migration and invasion of A431 cells was investigated. Our previous micro‑assay data revealed that the mRNA expression of MnSOD was higher in the invasive A431‑III cell line compared with that in the parental A431 cell line (A431‑P). In the present study, high protein levels of MnSOD and H2O2 production were observed in A431‑III cells; however, catalase protein levels were significantly lower in A431‑III cells compared with those in the A431‑P cell line. The knockdown of MnSOD increased H2O2 levels, enzyme activity, the mRNA levels of matrix metalloproteinase‑1, ‑2 and ‑9, and the migratory and invasive abilities of the cells. Inducing a reduction in H2O2 using diphenyleneiodonium (DPI) and N‑acetyl‑l‑cysteine decreased the migratory abilities of the cell lines, and DPI attenuated the migratory ability that had been increased by MnSOD small interfering RNA knockdown. Luteolin (Lu) and quercetin (Qu) increased the expression of catalase and reduced H2O2 levels, but without an observed change in the protein levels of MnSOD. Taken together, these data suggest that reduced MnSOD may induce ROS imbalance in cells and promote the metastatic ability of cancer cells. Lu and Qu may attenuate these processes and may be promising potential anticancer agents.

View Figures

View References

1	Aon MA, Cortassa S and O'Rourke B: Redox-optimized ROS balance: A unifying hypothesis. Biochim Biophys Acta. 1797:865–877. 2010. View Article : Google Scholar : PubMed/NCBI
2	Panieri E and Santoro MM: ROS homeostasis and metabolism: A dangerous liason in cancer cells. Cell Death Dis. 7:e2253. 2016. View Article : Google Scholar : PubMed/NCBI
3	Kim YS, Gupta Vallur P, Phaëton R, Mythreye K and Hempel N: Insights into the dichotomous regulation of SOD2 in cancer. Antioxidants. 6:862017. View Article : Google Scholar
4	Weydert C, Roling B, Liu J, Hinkhouse MM, Ritchie JM, Oberley LW and Cullen JJ: Suppression of the malignant phenotype in human pancreatic cancer cells by the overexpression of manganese superoxide dismutase. Mol Cancer Ther. 2:361–369. 2003.PubMed/NCBI
5	Zhong W, Oberley LW, Oberley TD and St Clair DK: Suppression of the malignant phenotype of human glioma cells by overexpression of manganese superoxide dismutase. Oncogene. 14:481–490. 1997. View Article : Google Scholar : PubMed/NCBI
6	Nelson KK, Ranganathan AC, Mansouri J, Rodriguez AM, Providence KM, Rutter JL, Pumiglia K, Bennett JA and Melendez JA: Elevated sod2 activity augments matrix metal-loproteinase expression: Evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis. Clin Cancer Res. 9:424–432. 2003.PubMed/NCBI
7	Connor KM, Hempel N, Nelson KK, Dabiri G, Gamarra A, Belarmino J, Van De Water L, Mian BM and Melendez JA: Manganese superoxide dismutase enhances the invasive and migratory activity of tumor cells. Cancer Res. 67:10260–10267. 2007. View Article : Google Scholar : PubMed/NCBI
8	Chen PM, Wu TC, Shieh SH, Wu YH, Li MC, Sheu GT, Cheng YW, Chen CY and Lee H: MnSOD promotes tumor invasion via upregulation of FoxM1-MMP2 axis and related with poor survival and relapse in lung adenocarcinomas. Mol Cancer Res. 11:261–271. 2013. View Article : Google Scholar
9	Malafa M, Margenthaler J, Webb B, Neitzel L and Christophersen M: MnSOD expression is increased in metastatic gastric cancer. J Surg Res. 88:130–134. 2000. View Article : Google Scholar : PubMed/NCBI
10	Li S, Mao Y, Zhou T, Luo C, Xie J, Qi W, Yang Z, Ma J, Gao G and Yang X: Manganese superoxide dismutase mediates anoikis resistance and tumor metastasis in nasopharyngeal carcinoma. Oncotarget. 7:32408–32420. 2016.PubMed/NCBI
11	Miar A, Hevia D, Muñoz-Cimadevilla H, Astudillo A, Velasco J, Sainz RM and Mayo JC: Manganese superoxide dismutase (SOD2/MnSOD)/catalase and SOD2/GPx1 ratios as biomarkers for tumor progression and metastasis in prostate, colon, and lung cancer. Free Radic Biol Med. 85:45–55. 2015. View Article : Google Scholar : PubMed/NCBI
12	Porporato PE, Payen VL, Pérez-Escuredo J, De Saedeleer CJ, Danhier P, Copetti T, Dhup S, Tardy M, Vazeille T, Bouzin C, et al: A mitochondrial switch promotes tumor metastasis. Cell Rep. 8:754–766. 2014. View Article : Google Scholar : PubMed/NCBI
13	Porporato PE and Sonveaux P: Paving the way for therapeutic prevention of tumor metastasis with agents targeting mitochondrial superoxide. Mol Cell Oncol. 2:e9680432014. View Article : Google Scholar
14	Heim KE, Tagliaferro AR and Bobilya DJ: Flavonoid antioxidants: Chemistry, metabolism and structure-activity relationships. J Nutr Biochem. 13:572–584. 2002. View Article : Google Scholar
15	Pietta PG: Flavonoids as antioxidants. J Nat Prod. 63:1035–1042. 2000. View Article : Google Scholar : PubMed/NCBI
16	Nijveldt RJ, van Nood E, van Hoorn DE, Boelens PG, van Norren K and van Leeuwen PAM: Flavonoids: A review of probable mechanisms of action and potential applications. Am J Clin Nutr. 74:418–425. 2001. View Article : Google Scholar : PubMed/NCBI
17	Procházková D, Boušová I and Wilhelmová N: Antioxidant and prooxidant properties of flavonoids. Fitoterapia. 82:513–523. 2011. View Article : Google Scholar : PubMed/NCBI
18	Kandaswami C, Lee LT, Lee PP, Hwang JJ, Ke FC, Huang YT and Lee MT: The antitumor activities of flavonoids. In Vivo. 19:895–909. 2005.PubMed/NCBI
19	Andarwulan N, Batari R, Sandrasari DA, Bolling B and Wijaya H: Flavonoid content and antioxidant activity of vegetables from Indonesia. Food Chem. 121:1231–1235. 2010. View Article : Google Scholar : PubMed/NCBI
20	Cao J, Chen W, Zhang Y, Zhang Y and Zhao X: Content of selected flavonoids in 100 edible vegetables and fruits. Food Sci Technol Res. 16:395–402. 2010. View Article : Google Scholar
21	Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, Kandaswami C, Middleton E Jr and Lee MT: Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. Br J Pharmacol. 128:999–1010. 1999. View Article : Google Scholar : PubMed/NCBI
22	Lee LT, Huang YT, Hwang JJ, Lee PP, Ke FC, Nair MP, Kanadaswam C and Lee MT: Blockade of the epidermal growth factor receptor tyrosine kinase activity by quercetin and luteolin leads to growth inhibition and apoptosis of pancreatic tumor cells. Anticancer Res. 22:1615–1627. 2002.PubMed/NCBI
23	Fotsis T, Pepper MS, Aktas E, Breit S, Rasku S, Adlercreutz H, Wähälä K, Montesano R and Schweigerer L: Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angio-genesis. Cancer Res. 57:2916–2921. 1997.PubMed/NCBI
24	Kawaii S, Tomono Y, Katase E, Ogawa K and Yano M: Antiproliferative activity of flavonoids on several cancer cell lines. Biosci Biotechnol Biochem. 63:896–899. 1999. View Article : Google Scholar : PubMed/NCBI
25	Cherng JM, Shieh DE, Chiang W, Chang MY and Chiang LC: Chemopreventive effects of minor dietary constituents in common foods on human cancer cells. Biosci Biotechnol Biochem. 71:1500–1504. 2007. View Article : Google Scholar : PubMed/NCBI
26	Takahashi T, Kobori M, Shinmoto H and Tsushida T: Structure-activity relationships of flavonoids and the induction of granulocytic- or monocytic-differentiation in HL60 human myeloid leukemia cells. Biosci Biotechnol Biochem. 62:2199–2204. 1998. View Article : Google Scholar
27	Leung HW, Kuo CL, Yang WH, Lin CH and Lee HZ: Antioxidant enzymes activity involvement in luteolin-induced human lung squamous carcinoma CH27 cell apoptosis. Eur J Pharmacol. 534:12–18. 2006. View Article : Google Scholar : PubMed/NCBI
28	Kang KP, Park SK, Kim DH, Sung MJ, Jung YJ, Lee AS, Lee JE, Ramkumar KM, Lee S, Park MH, et al: Luteolin ameliorates cisplatin-induced acute kidney injury in mice by regulation of p53-dependent renal tubular apoptosis. Nephrol Dial Transplant. 26:814–822. 2011. View Article : Google Scholar
29	Sandhir R and Mehrotra A: Quercetin supplementation is effective in improving mitochondrial dysfunctions induced by 3-nitropropionic acid: Implications in Huntington's disease. Biochim Biophys Acta. 1832:421–430. 2013. View Article : Google Scholar
30	Mediratta PK, Banerjee BD, Halder S, Kar R and Bhattacharya SK: Effect of chromium on glutathione-S-transferase and catalase activity and their respective gene expressions in the brain tissue of F1 generation mice following prenatal exposure: Modulation by quercetin. J Clin Toxicol. 7:3652017. View Article : Google Scholar
31	Kao WT, Lin CY, Lee LT, Lee PP, Hung CC, Lin YS, Chen SH, Ke FC, Hwang JJ and Lee MT: Investigation of MMP-2 and -9 in a highly invasive A431 tumor cell sub-line selected from a Boyden chamber assay. Anticancer Res. 28:2109–2120. 2008.PubMed/NCBI
32	Lin CY, Tsai PH, Kandaswami CC, Lee PP, Huang CJ, Hwang JJ and Lee MT: Matrix metalloproteinase-9 cooperates with transcription factor Snail to induce epithelial-mesenchymal transition. Cancer Sci. 102:815–827. 2011. View Article : Google Scholar : PubMed/NCBI
33	Lin CY, Tsai PH, Kandaswami CC, Chang GD, Cheng CH, Huang CJ, Lee PP, Hwang JJ and Lee MT: Role of tissue transglu-taminase 2 in the acquisition of a mesenchymal-like phenotype in highly invasive A431 tumor cells. Mol Cancer. 10:872011. View Article : Google Scholar
34	Lin YS, Tsai PH, Kandaswami CC, Cheng CH, Ke FC, Lee PP, Hwang JJ and Lee MT: Effects of dietary flavonoids, luteolin, and quercetin on the reversal of epithelial-mesenchymal transition in A431 epidermal cancer cells. Cancer Sci. 102:1829–1839. 2011. View Article : Google Scholar : PubMed/NCBI
35	Chen KC, Hsu WH, Ho JY, Lin CW, Chu CY, Kandaswami CC, Lee MT and Cheng CH: Flavonoids luteolin and quercetin inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction. J Food Drug Anal. 26:1180–1191. 2018. View Article : Google Scholar : PubMed/NCBI
36	Lin CW, Lai GM, Chen KC, Lin TH, Fan JJ, Hsu RL, Chou CM, Lin CM, Kandaswami CC, Lee MT, et al: RPS12 increases the invasiveness in cervical cancer activated by c-Myc and inhibited by the dietary flavonoids luteolin and quercetin. J Funct Foods. 19:236–247. 2015. View Article : Google Scholar
37	Lin TH, Hsu WH, Tsai PH, Huang YT, Lin CW, Chen KC, Tsai IH, Kandaswami CC, Huang CJ, Chang GD, et al: Dietary flavonoids, luteolin and quercetin, inhibit invasion of cervical cancer by reduction of UBE2S through epithelial-mesenchymal transition signaling. Food Funct. 8:1558–1568. 2017. View Article : Google Scholar : PubMed/NCBI
38	Beauchamp C and Fridovich I: Superoxide dismutase: Improved assays and an assay applicable to acrylamide gels. Anal Biochem. 44:276–287. 1971. View Article : Google Scholar : PubMed/NCBI
39	Chin JR, Murphy G and Werb Z: Stromelysin, a connective tissue-degrading metalloendopeptidase secreted by stimulated rabbit synovial fibroblasts in parallel with collagenase. Biosynthesis, isolation, characterization, and substrates. J Biol Chem. 260:12367–12376. 1985.PubMed/NCBI
40	Nishikawa M: Reactive oxygen species in tumor metastasis. Cancer Lett. 266:53–59. 2008. View Article : Google Scholar : PubMed/NCBI
41	Venkatesan B, Mahimainathan L, Das F, Ghosh-Choudhury N and Ghosh Choudhury G: Downregulation of catalase by reactive oxygen species via PI 3 kinase/Akt signaling in mesangial cells. J Cell Physiol. 211:457–467. 2007. View Article : Google Scholar
42	Shen Y, Xu W, You H, Su D, Xing J, Li M, Li L and Liang X: FoxO1 inhibits transcription and membrane trafficking of epithelial Na⁺ channel. J Cell Sci. 128:3621–3630. 2015. View Article : Google Scholar : PubMed/NCBI
43	Chang B, Yang H, Jiao Y, Wang K, Liu Z, Wu P, Li S and Wang A: SOD2 deregulation enhances migration, invasion and has poor prognosis in salivary adenoid cystic carcinoma. Sci Rep. 6:259182016. View Article : Google Scholar : PubMed/NCBI
44	Chen PM, Wu TC, Wang YC, Cheng YW, Sheu GT, Chen CY and Lee H: Activation of NF-κB by SOD2 promotes the aggressiveness of lung adenocarcinoma by modulating NKX21-mediated IKKβ expression. Carcinogenesis. 34:2655–2663. 2013. View Article : Google Scholar : PubMed/NCBI
45	Kang KA, Piao MJ, Ryu YS, Hyun YJ, Park JE, Shilnikova K, Zhen AX, Kang HK, Koh YS, Jeong YJ, et al: Luteolin induces apoptotic cell death via antioxidant activity in human colon cancer cells. Int J Oncol. 51:1169–1178. 2017. View Article : Google Scholar : PubMed/NCBI
46	Li Y, Shen L and Luo H: Luteolin ameliorates dextran sulfate sodium-induced colitis in mice possibly through activation of the Nrf2 signaling pathway. Int Immunopharmacol. 40:24–31. 2016. View Article : Google Scholar : PubMed/NCBI
47	Dias AS, Porawski M, Alonso M, Marroni N, Collado PS and González-Gallego J: Quercetin decreases oxidative stress, NF-κB activation, and iNOS overexpression in liver of strepto-zotocin-induced diabetic rats. J Nutr. 135:2299–2304. 2005. View Article : Google Scholar : PubMed/NCBI
48	Ben Abdallah F, Zribi N and Ammar-Keskes L: Antioxidative potential of Quercetin against hydrogen peroxide induced oxidative stress in spermatozoa in vitro. Andrologia. 43:261–265. 2011. View Article : Google Scholar : PubMed/NCBI
49	Nabavi SF, Nabavi SM, Latifi AM, Mirzaei M, Habtemariam S and Moghaddam AH: Mitigating role of quercetin against sodium fluoride-induced oxidative stress in the rat brain. Pharm Biol. 50:1380–1383. 2012. View Article : Google Scholar : PubMed/NCBI