Curcumin inhibits cervical cancer cell proliferation, migration and invasion by suppressing the PI3K/AKT signaling pathway via the miR-29b/KDM2A axis

doi:10.5246/jcps.2020.06.038

Abstract

Abstract:

In this study, we aimed to examine whether curcumin exerted its anti-tumor effects by regulating miR-29b/KDM2A in cervical cancer cells. The cell viability, migration and invasion were estimated in HeLa cervical cancer cells treated with curcumin. The effects of microRNA-29b (miR-29b) on biological behaviors of HeLa SiHa cells were also assessed. Potential target genes of miR-29b were predicted and confirmed using a luciferase reporter assay, and the effects of curcumin and miR-29b on the PI3K/AKTsignaling pathway were analyzed. Curcumin treatment inhibited cell proliferation, migration and invasion of HeLa cells (P<0.05). The miR-29b expression was promoted by curcumin treatment in HeLa cells (P<0.01), and miR-29b depletion could restore the effects of curcumin on cell proliferation, migration and invasion of HeLa cells (P<0.05). KDM2A was proved as a direct target gene of miR-29b, and the activity of the PI3K/AKT signaling could be regulated by curcumin and miR-29b (P<0.05). All the data revealed that curcumin played a protective role in cervical cancer. The proliferation, migration and invasion of cervical cancer cells were inhibited by curcumin through the miR-29b/KDM2A/PI3K/AKT pathway.

Key words: Curcumin, Proliferation, Migration, Invasion, MiR-29b, Cervical cancer

CLC Number:

R965

Supporting:

Xichun Guo, Jinghua Chen, Rujun Gao, Xiuyuan Han. Curcumin inhibits cervical cancer cell proliferation, migration and invasion by suppressing the PI3K/AKT signaling pathway via the miR-29b/KDM2A axis[J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(6): 398-410.

References

[1] Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin. 2015, 65, 87-108.

[2] Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 2012, 62, 10-29.

[3] de Guadalupe Chávez-López, M.; Hernández-Gallegos, E.; Vázquez-Sánchez, A.Y.; Gariglio, P.; Camacho, J. Antiproliferative and proapoptotic effects of astemizole on cervical cancer cells. Int. J. Gynecol. Cancer. 2014, 24, 824-828.

[4] Shin, H.J.; Joo, J.; Yoon, J.H.; Yoo, C.W.; Kim, J.Y. Physical status of human papillomavirus integration in cervical cancer is associated with treatment outcome of the patients treated with radiotherapy. PLoS One. 2014, 9, e78995.

[5] Falcetta, F.S.; Medeiros, L.R.; Edelweiss, M.I.; Pohlmann, P.R.; Stein, A.T.; Rosa, D.D. Adjuvant platinum-based chemotherapy for early stage cervical cancer. Cochrane Database. Syst. Rev. 2016, 11, CD005342.

[6] Jakubowicz, J.; Blecharz, P.; Skotnicki, P.; Reinfuss, M.; Walasek, T.; Luczynska, E. Toxicity of concurrent chemoradiotherapy for locally advanced cervical cancer. Eur. J. Gynaecol. Oncol. 2014, 35, 393-399.

[7] Oliveira, A.S.; Sousa, E.; Vasconcelos, M.H.; Pinto, M. Curcumin: a natural lead for potential new drug candidates. Curr. Med. Chem. 2015, 22, 4196-4232.

[8] Priyadarsini, K.I. The chemistry of curcumin: from extraction to therapeutic agent. Molecules. 2014, 19, 20091-20112.

[9] Lu, W.; Jiang, J.P.; Hu, J.; Wang, J.; Zheng, M.Z. Curcumin protects against lipopolysaccharide-induced vasoconstriction dysfunction via inhibition of thrombospondin-1 and transforming growth factor-β1. Exp. Ther. Med. 2015, 9, 377-383.

[10] Borra, S.K.; Mahendra, J.; Gurumurthy, P.; Jayamathi,, Iqbal, S.S.; Mahendra, L. Effect of curcumin against oxidation of biomolecules by hydroxyl radicals. J. Clin. Diagn. Res. 2014, 8, CC01-CC05.

[11] Nahar, P.P.; Slitt, A.L.; Seeram, N.P. Anti-inflammatory effects of novel standardized solid lipid curcumin formulations. J. Med. Food. 2015, 18, 786-792.

[12] Zhang, X.J.; Wang, R.B.; Chen, G.L.; Dejean, L.; Chen, Q.H. The effects of curcumin-based compounds on proliferation and cell death in cervical cancer cells. Anticancer. Res. 2015, 35, 5293-5298.

[13] Bhaskaran, M.; Mohan, M. MicroRNAs: history, biogenesis, and their evolving role in animal development and disease. Vet. Pathol. 2014, 51, 759-774.

[14] Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004, 116, 281-297.

[15] Zhang, X.L.; Shi, H.J.; Tang, H.S.; Fang, Z.Y.; Wang, J.P.; Cui, S.Z. MiR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway. Int. J. Mol. Med. 2015, 35, 1301-1308.

[16] Aghaee-Bakhtiari, S.H.; Arefian, E.; Naderi, M.; Noorbakhsh, F.; Nodouzi, V.; Asgari, M.; Fard-Esfahani, P.; Mahdian, R.; Soleimani, M. MAPK and JAK/STAT pathways targeted by miR-23a and miR-23b in prostate cancer: computational and in vitro approaches. Tumour. Biol. 2015, 36, 4203-4212.

[17] Wang, W.; Ren, F.; Wu, Q.H.; Jiang, D.Z.; Li, H.J.; Shi, H.R. MicroRNA-497 suppresses angiogenesis by targeting vascular endothelial growth factor A through the PI3K/AKT and MAPK/ERK pathways in ovarian cancer. Oncol. Rep. 2014, 32, 2127-2133.

[18] Chen, J.Z.; Xu, T.F.; Chen, C. The critical roles of miR-21 in anti-cancer effects of curcumin. Ann. Transl. Med. 2015, 3, 330.

[19] Zhang, L.; Huang, H.; Zhang, L.J.; Hou, T.; Wu, S.; Huang, Q.D.; Song, L.B.; Liu, J.H. URG4 overexpression is correlated with cervical cancer progression and poor prognosis in patients with early-stage cervical cancer. BMC Cancer. 2014, 14, 885.

[20] Troselj, K.G.; Kujundzic, R.N. Curcumin in combined cancer therapy. Curr. Pharm. Des. 2014, 20, 6682-6696.

[21] Lim, T.G.; Lee, S.Y.; Huang, Z.N.; Lim, D.Y.; Chen, H.Y.; Jung, S.K.; Bode, A.M.; Lee, K.W.; Dong, Z.G. Curcumin suppresses proliferation of colon cancer cells by targeting CDK2. Cancer Prev. Res. (Phila). 2014, 7, 466-474.

[22] Chen, B.; Zhang, Y.Z.; Wang, Y.; Rao, J.; Jiang, X.M.; Xu, Z.H. Curcumin inhibits proliferation of breast cancer cells through Nrf2-mediated down-regulation of Fen1 expression. J. Steroid. Biochem. Mol. Biol. 2014, 143, 11-18.

[23] Lu, Y.M.; Wei, C.J.; Xi, Z.Q. Curcumin suppresses proliferation and invasion in non-small cell lung cancer by modulation of MTA1-mediated Wnt/β-catenin pathway. In Vitro Cell. Dev. Biol. Anim. 2014, 50, 840-850.

[24] Shang, H.S.; Chang, C.H.; Chou, Y.R.; Yeh, M.Y.; Au, M.K.; Lu, H.F.; Chu, Y.L.; Chou, H.M.; Chou, H.C.; Shih, Y.L.; Chung, J.G. Curcumin causes DNA damage and affects associated protein expression in HeLa human cervical cancer cells. Oncol. Rep. 2016, 36, 2207-2215.

[25] Li, X.T.; Xie, W.; Xie, C.F.; Huang, C.; Zhu, J.Y.; Liang, Z.F.; Deng, F.F.; Zhu, M.M.; Zhu, W.W.; Wu, R.; Wu, J.S.; Geng, S.S.; Zhong, C.Y. Curcumin modulates miR-19/PTEN/AKT/p53 Axis to suppress bisphenol A-induced MCF-7 breast cancer cell proliferation. Phytother. Res. 2014, 28, 1553-1560.

[26] Jin, H.; Qiao, F.; Wang, Y.; Xu, Y.D.; Shang, Y. Curcumin inhibits cell proliferation and induces apoptosis of human non-small cell lung cancer cells through the upregulation of miR-192-5p and suppression of PI3K/Akt signaling pathway. Oncol. Rep. 2015, 34, 2782-2789.

[27] Ma, J.; Fang, B.B.; Zeng, F.P.; Pang, H.J.; Zhang, J.; Shi, Y.; Wu, X.P.; Cheng, L.; Ma, C.; Xia, J.; Wang, Z.W. Curcumin inhibits cell growth and invasion through up-regulation of miR-7 in pancreatic cancer cells. Toxicol. Lett. 2014, 231, 82-91.

[28] Wang, B.; Li, W.; Liu, H.; Yang, L.; Liao, Q.; Cui, S.; Wang, H.; Zhao, L. MiR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial-mesenchymal transition. Cell Death Dis. 2014, 5, e1335.

[29] Jia, L.F.; Huang, Y.P.; Zheng, Y.F.; Lyu, M.Y.; Wei, S.B.; Meng, Z.; Gan, Y.H. MiR-29b suppresses proliferation, migration, and invasion of tongue squamous cell carcinoma through PTEN-AKT signaling pathway by targeting Sp1. Oral Oncol. 2014, 50, 1062-1071.

[30] Liu, Y.L.; Zhang, J.L.; Sun, X.J.; Su, Q.P.; You, C.P. Down-regulation of miR-29b in carcinoma associated fibroblasts promotes cell growth and metastasis of breast cancer. Oncotarget. 2017, 8, 39559-39570.

[31] Li, Y.Y.; Zhang, Z.Z.; Xiao, Z.H.; Lin, Y.; Luo, T.S.; Zhou, Q.; Zhang, X.J. Chemotherapy-mediated miR-29b expression inhibits the invasion and angiogenesis of cervical cancer. Oncotarget. 2017, 8, 14655-14665.

[32] Liu, H.; Cheng, X.H. MiR-29b reverses oxaliplatin-resistance in colorectal cancer by targeting SIRT1. Oncotarget. 2018, 9, 12304-12315.

[33] Wang, L.H.; Wang, Z.H.; Huang, L.Y.; Wu, C.R.; Zhang, B. MiR-29b suppresses proliferation and mobility by targeting SOX12 and DNMT3b in pancreatic cancer. Anticancer Drugs. 2019, 30, 281-288.

[34] Kong, Y.; Zou, S.Y.; Yang, F.H.; Xu, X.; Bu, W.H.; Jia, J.H.; Liu, Z.F. RUNX3-mediated up-regulation of miR-29b suppresses the proliferation and migration of gastric cancer cells by targeting KDM2A. Cancer Lett. 2016, 381, 138-148.

[35] Ou, R.Y.; Zhu, L.Y.; Zhao, L.; Li, W.F.; Tao, F.X.; Lu, Y.Y.; He, Q.; Li, J.R.; Ren, Y.; Xu, Y.S. HPV16 E7-induced upregulation of KDM2A promotes cervical cancer progression by regulating miR-132-radixin pathway. J. Cell Physiol. 2019, 234, 2659-2671.

[36] Lu, D.H.; Yang, J.; Gao, L.K.; Min, J.; Tang, J.M.; Hu, M.; Li, Y.; Li, S.T.; Chen, J.; Hong, L. Lysine demethylase 2A promotes the progression of ovarian cancer by regulating the PI3K pathway and reversing epithelial-mesenchymal transition. Oncol. Rep. 2019, 41, 917-927.

[37] Polivka, J. Jr, Janku, F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol. Ther. 2014, 142, 164-175.

[38] Teng, P.; Jiao, Y.; Hao, M.; Tang, X. MicroRNA-383 suppresses the PI3K-AKT-MTOR signaling pathway to inhibit development of cervical cancer via down-regulating PARP2. J. Cell Biochem. 2018, 119, 5243-5252.

[39] Cui, F.; Li, X.L.; Zhu, X.Y.; Huang, L.L.; Huang, Y.F.; Mao, C.Y.; Yan, Q.; Zhu, J.H.; Zhao, W.X.; Shi, H. MiR-125b inhibits tumor growth and promotes apoptosis of cervical cancer cells by targeting phosphoinositide 3-kinase catalytic subunit delta. Cell Physiol. Biochem. 2012, 30, 1310-1318.

[40] Xu, X.B.; Qin, J.; Liu, W.Y. Curcumin inhibits the invasion of thyroid cancer cells via down-regulation of PI3K/Akt signaling pathway. Gene. 2014, 546, 226-232.

[41] Zhao, Z.M.; Li, C.G.; Xi, H.; Gao, Y.X.; Xu, D.B. Curcumin induces apoptosis in pancreatic cancer cells through the induction of forkhead box O1 and inhibition of the PI3K/Akt pathway. Mol. Med. Rep. 2015, 12, 5415-5422.