Cantharidin inhibits melanoma cell proliferation via the miR‑21‑mediated PTEN pathway

Mu,Zhen; Sun,Qing

doi:10.3892/mmr.2018.9440

Cantharidin inhibits melanoma cell proliferation via the miR‑21‑mediated PTEN pathway

Authors:
- Zhen Mu
- Qing Sun
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Affiliations: Department of Dermatology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: September 3, 2018 https://doi.org/10.3892/mmr.2018.9440
Pages: 4603-4610

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Abstract

Cantharidin (CTD) is an active component isolated from the blister beetle that has been demonstrated to exert antitumor effects on multiple types of cancer. The current study aimed to investigate whether the potential inhibitory effects of CTD exist in human melanoma cells and to assess the underlying antitumor mechanisms of CTD. Using the Cell Counting Kit‑8 assay, it was demonstrated that CTD treatment reduced A375 cell proliferation significantly in a dose‑dependent manner. The colony formation assay demonstrated that CTD treatment could decrease the number of A375 cell colonies. Using subcutaneous xenograft tumor models, it was also demonstrated that CTD retarded solid tumor growth significantly. Furthermore, CTD treatment could induce A375 cell apoptosis, as detected by Annexin V‑fluorescein isothiocyanate/propidium iodide staining and western blot analysis. Notably, CTD treatment reduced microRNA (miR)‑21 expression and enhanced phosphatase and tensin homolog (PTEN) protein expression levels in A375 cells. Furthermore, overexpressing miR‑21 in A375 cells with the miR‑21 agomir blocked the antitumor effect of CTD both in vitro and in vivo. Finally, it was demonstrated that the inhibitory effects of CTD on A375 cells may be regulated by attenuating miR‑21‑mediated PTEN suppression. Based on these observations, it was suggested that CTD be used as a novel anti‑proliferation agent of human melanoma via targeting the miR‑21‑PTEN signaling pathway.

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1	Apalla Z, Lallas A, Sotiriou E, Lazaridou E and Ioannides D: Epidemiological trends in skin cancer. Dermatol Pract Concept. 7:1–6. 2017. View Article : Google Scholar : PubMed/NCBI
2	Miller AJ and Mihm MC Jr: Melanoma. N Engl J Med. 355:51–65. 2006. View Article : Google Scholar : PubMed/NCBI
3	Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
4	Kalal BS, Upadhya D and Pai VR: Chemotherapy resistance mechanisms in advanced skin cancer. Oncol Rev. 11:3262017. View Article : Google Scholar : PubMed/NCBI
5	Deng LP, Dong J, Cai H and Wang W: Cantharidin as an antitumor agent: A retrospective review. Curr Med Chem. 20:159–166. 2013. View Article : Google Scholar : PubMed/NCBI
6	Shen M, Wu MY, Chen LP, Zhi Q, Gong FR, Chen K, Li DM, Wu Y, Tao M and Li W: Cantharidin represses invasion of pancreatic cancer cells through accelerated degradation of MMP2 mRNA. Sci Rep. 5:118362015. View Article : Google Scholar : PubMed/NCBI
7	Zheng LH, Bao YL, Wu Y, Yu CL, Meng X and Li YX: Cantharidin reverses multidrug resistance of human hepatoma HepG2/ADM cells via down-regulation of P-glycoprotein expression. Cancer Lett. 272:102–109. 2008. View Article : Google Scholar : PubMed/NCBI
8	Xie D, Xie J, Wan Y, Ma L, Qi X, Wang K and Yang S: Norcantharidin blocks Wnt/β-catenin signaling via promoter demethylation of WIF-1 in glioma. Oncol Rep. 35:2191–2197. 2016. View Article : Google Scholar : PubMed/NCBI
9	Ji BC, Hsiao YP, Tsai CH, Chang SJ, Hsu SC, Liu HC, Huang YP, Lien JC and Chung JG: Cantharidin impairs cell migration and invasion of A375.S2 human melanoma cells by suppressing MMP-2 and −9 through PI3K/NF-κB signaling pathways. Anticancer Res. 35:729–738. 2015.PubMed/NCBI
10	Hsiao YP, Tsai CH, Wu PP, Hsu SC, Liu HC, Huang YP, Yang JH and Chung JG: Cantharidin induces G2/M phase arrest by inhibition of Cdc25c and Cyclin A and triggers apoptosis through reactive oxygen species and the mitochondria-dependent pathways of A375.S2 human melanoma cells. Int J Oncol. 45:2393–2402. 2014. View Article : Google Scholar : PubMed/NCBI
11	Wandler A, Riber-Hansen R, Hager H, Hamilton-Dutoit SJ, Schmidt H, Nielsen BS, Stougaard M and Steiniche T: Quantification of microRNA-21 and microRNA-125b in melanoma tissue. Melanoma Res. 27:417–428. 2017. View Article : Google Scholar : PubMed/NCBI
12	Latchana N, Ganju A, Howard JH and Carson WE III: MicroRNA dysregulation in melanoma. Surg Oncol. 25:184–189. 2016. View Article : Google Scholar : PubMed/NCBI
13	Li H, Yuan SM, Yang M, Zha H, Li XR, Sun H, Duan L, Gu Y, Li AF, Weng YG, et al: High intensity focused ultrasound inhibits melanoma cell migration and metastasis through attenuating microRNA-21-mediated PTEN suppression. Oncotarget. 7:50450–50460. 2016.PubMed/NCBI
14	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 : PubMed/NCBI
15	Zhang X, Lin C, Lu A, Lin G, Chen H, Liu Q, Yang Z and Zhang H: Liposomes equipped with cell penetrating peptide BR2 enhances chemotherapeutic effects of cantharidin against hepatocellular carcinoma. Drug Deliv. 24:986–998. 2017. View Article : Google Scholar : PubMed/NCBI
16	Li W, Xie L, Chen Z, Zhu Y, Sun Y, Miao Y, Xu Z and Han X: Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. Cancer Sci. 101:1226–1233. 2010. View Article : Google Scholar : PubMed/NCBI
17	Garajová I, Ferracin M, Porcellini E, Palloni A, Abbati F, Biasco G and Brandi G: Non-Coding RNAs as predictive biomarkers to current treatment in metastatic colorectal cancer. Int J Mol Sci. 18(pii): E15472017. View Article : Google Scholar : PubMed/NCBI
18	van Beijnum JR, Giovannetti E, Poel D, Nowak-Sliwinska P and Griffioen AW: miRNAs: Micro-managers of anticancer combination therapies. Angiogenesis. 20:269–285. 2017. View Article : Google Scholar : PubMed/NCBI
19	Deng J, Wang Y, Lei J, Lei W and Xiong JP: Insights into the involvement of noncoding RNAs in 5-fluorouracil drug resistance. Tumour Biol. 39:10104283176975532017. View Article : Google Scholar : PubMed/NCBI
20	Mao XH, Chen M, Wang Y, Cui PG, Liu SB and Xu ZY: MicroRNA-21 regulates the ERK/NF-κB signaling pathway to affect the proliferation, migration, and apoptosis of human melanoma A375 cells by targeting SPRY1, PDCD4, and PTEN. Mol Carcinog. 56:886–894. 2017. View Article : Google Scholar : PubMed/NCBI
21	Martin del Campo SE, Latchana N, Levine KM, Grignol VP, Fairchild ET, Jaime-Ramirez AC, Dao TV, Karpa VI, Carson M, Ganju A, et al: MiR-21 enhances melanoma invasiveness via inhibition of tissue inhibitor of metalloproteinases 3 expression: In vivo effects of MiR-21 inhibitor. PLoS One. 10:e01159192015. View Article : Google Scholar : PubMed/NCBI
22	Li Y, Wu R, Liu Z, Fan J and Yang H: Enforced expression of microRNA-21 influences the replication of varicella-zoster virus by triggering signal transducer and activator of transcription 3. Exp Ther Med. 7:1291–1296. 2014. View Article : Google Scholar : PubMed/NCBI
23	Fu X, He Y, Wang X, Peng D, Chen X, Li X and Wang Q: Overexpression of miR-21 in stem cells improves ovarian structure and function in rats with chemotherapy-induced ovarian damage by targeting PDCD4 and PTEN to inhibit granulosa cell apoptosis. Stem Cell Res Ther. 8:1872017. View Article : Google Scholar : PubMed/NCBI
24	Bu LL, Yu GT, Wu L, Mao L, Deng WW, Liu JF, Kulkarni AB, Zhang WF, Zhang L and Sun ZJ: STAT3 Induces Immunosuppression by Upregulating PD-1/PD-L1 in HNSCC. J Dent Res. 96:1027–1034. 2017. View Article : Google Scholar : PubMed/NCBI
25	George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ, Shukla S, Lipschitz M, Amin-Mansour A, Raut CP, Carter SL, et al: Loss of PTEN Is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity. 46:197–204. 2017. View Article : Google Scholar : PubMed/NCBI
26	Zhou K, Zhong Q, Wang YC, Xiong XY, Meng ZY, Zhao T, Zhu WY, Liao MF, Wu LR, Yang YR, et al: Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis. J Cereb Blood Flow Metab. 37:967–979. 2017. View Article : Google Scholar : PubMed/NCBI
27	Mondal S, Ghosh-Roy S, Loison F, Li Y, Jia Y, Harris C, Williams DA and Luo HR: PTEN negatively regulates engulfment of apoptotic cells by modulating activation of Rac GTPase. J Immunol. 187:5783–5794. 2011. View Article : Google Scholar : PubMed/NCBI
28	Conde-Perez A and Larue L: PTEN and melanomagenesis. Future Oncol. 8:1109–1120. 2012. View Article : Google Scholar : PubMed/NCBI
29	Li WX, Chen X, Yang Y, Huang HM, Li HD, Huang C, Meng XM and Li J: Hesperitin derivative-11 suppress hepatic stellate cell activation and proliferation by targeting PTEN/AKT pathway. Toxicology. 381:75–86. 2017. View Article : Google Scholar : PubMed/NCBI
30	He Z, Chen AY, Rojanasakul Y, Rankin GO and Chen YC: Gallic acid, a phenolic compound, exerts anti-angiogenic effects via the PTEN/AKT/HIF-1α/VEGF signaling pathway in ovarian cancer cells. Oncol Rep. 35:291–297. 2016. View Article : Google Scholar : PubMed/NCBI
31	Guo YB, Ji TF, Zhou HW and Yu JL: Effects of microRNA-21 on nerve cell regeneration and neural function recovery in diabetes mellitus combined with cerebral infarction rats by targeting PDCD4. Mol Neurobiol. 55:2494–2505. 2018. View Article : Google Scholar : PubMed/NCBI