Curcumin is a potent antitumor agent. The objective of this study was to explore the interaction between curcumin and PGK1, an oncogene in the FOXD3/miR-143 axis, in prostate cancer therapy.
MiRNA microarray analysis was used to identify miRNAs upregulated by curcumin treatment. MiR-143 was dramatically upregulated by curcumin. Cells were treated with antimiR-143 in combination to curcumin, followed by examining cell viability and migration. Bioinformatics analysis was used to investigate target genes of miR-143. The interaction between miR-143 and PGK1 was evaluated with dual-luciferase assay. Since FOXD3 is important in the regulation of miR-143, we explored whether curcumin regulated FOXD3 expression. FOXD3 was also ectopically overexpressed to investigate its effects on curcumin’s regulation of miR-143.
Curcumin treatment significantly upregulated miR-143 and decreased prostate cancer cell proliferation and migration. Those effects were attenuated by anti-miR-143 transfection. Both miR-143 overexpression and curcumin treatment inhibited PGK1 expression and ectopic expression of PGK1 antagonized curcumin’s antitumor effects. FOXD3 was upregulated by miR-143. Ectopic expression of FOXD3 synergized with curcumin in upregulating miR-143 expression.
Curcumin inhibits prostate cancer by upregulating miR-143. PGK1 is downregulated by miR-143, and FOXD3 upregulation is essential for the antitumor effect of curcumin.
This is a preview of subscription content,to check access.
Access this article
Similar content being viewed by others
Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66(1):7–30
Culine S, El Demery M, Lamy PJ, Iborra F, Avances C, Pinguet F (2007) Docetaxel and cisplatin in patients with metastatic androgen independent prostate cancer and circulating neuroendocrine markers. J Urol 178(3):844–848. doi:10.1016/j.juro.2007.05.044
Dorai T, Cao YC, Dorai B, Buttyan R, Katz AE (2001) Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo. Prostate 47(4):293–303. doi:10.1002/pros.1074.abs
Chendil D, Ranga RS, Meigooni D, Sathishkumar S, Ahmed MM (2004) Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene 23(8):1599–1607. doi:10.1038/sj.onc.1207284
Hatcher H, Planalp R, Cho J, Torti FM, Torti SV (2008) Curcumin: from ancient medicine to current clinical trials. CMLS 65 (11):1631–1652. doi:10.1007/s00018-008-7452-4
Sun M, Estrov Z, Ji Y, Coombes KR, Harris DH, Kurzrock R (2008) Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol Cancer Ther 7(3):464–473. doi:10.1158/1535-7163.MCT-07-2272
Saini S, Arora S, Majid S, Shahryari V, Chen Y, Deng GR, Yamamura S, Ueno K, Dahiya R (2011) Curcumin modulates MicroRNA-203-mediated regulation of the Src-Akt axis in bladder cancer. Cancer Prev Res 4(10):1698–1709. doi:10.1158/1940-6207.CAPR-11-0267
Li X, Xie W, Xie C, Huang C, Zhu J, Liang Z, Deng F, Zhu M, Zhu W, Wu R, Wu J, Geng S, Zhong C (2014) Curcumin modulates miR-19/PTEN/AKT/p53 axis to suppress bisphenol A-induced MCF-7 breast cancer cell proliferation. PTR 28(10):1553–1560. doi:10.1002/ptr.5167
Saini S, Arora S, Majid S, Shahryari V, Chen Y, Deng G, Yamamura S, Ueno K, Dahiya R (2011) Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer. Cancer Prev Res (Phila) 4(10):1698–1709. doi:10.1158/1940-6207.CAPR-11-0267
Zhang JA, Du YP, Wu CG, Ren XL, Ti XY, Shi JR, Zhao F, Yin H (2010) Curcumin promotes apoptosis in human lung adenocarcinoma cells through miR-186 signaling pathway. Oncol Rep 24(5):1217–1223. doi:10.3892/or_00000975
Ambs S, Prueitt RL, Yi M, Hudson RS, Howe TM, Petrocca F, Wallace TA, Liu CG, Volinia S, Calin GA, Yfantis HG, Stephens RM, Croce CM (2008) Genomic profiling of MicroRNA and messenger RNA reveals deregulated MicroRNA expression in prostate cancer. Cancer Res 68(15):6162–6170. doi:10.1158/0008-5472.CAN-08-0144
Zhou P, Chen W-G, Li X-W (2015) MicroRNA-143 acts as a tumor suppressor by targeting hexokinase 2 in human prostate cancer. Am J Cancer Res 5(6):2056
Wang JH, Ying GG, Wang JC, Jung YH, Lu JA, Zhu JA, Pienta KJ, Taichman RS (2010) Characterization of phosphoglycerate kinase-1 expression of stromal cells derived from tumor microenvironment in prostate cancer progression. Cancer Res 70(2):471–480. doi:10.1158/0008-5472.CAN-09-2863
Singh PK, Mehla K, Hollingsworth MA, Johnson KR (2011) Regulation of Aerobic Glycolysis by microRNAs in Cancer. Mol Cell Pharmacol 3(3):125–134
Jordan BC, Mock CD, Thilagavathi R, Selvam C (2016) Molecular mechanisms of curcumin and its semisynthetic analogues in prostate cancer prevention and treatment. Life Sci 152:135–144. doi:10.1016/j.lfs.2016.03.036
Abel EV, Aplin AE (2010) FOXD3 is a mutant B-RAF-regulated inhibitor of G1-S progression in melanoma cells. Cancer Res 70(7):2891–2900
Agarwal V, Bell GW, Nam JW, Bartel DP (2015) Predicting effective microRNA target sites in mammalian mRNAs. Elife. doi:10.7554/eLife.05005
Mathelier A, Fornes O, Arenillas DJ, Chen CY, Denay G, Lee J, Shi W, Shyr C, Tan G, Worsley-Hunt R, Zhang AW, Parcy F, Lenhard B, Sandelin A, Wasserman WW (2016) JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles. Nucleic Acids Res 44(D1):D110–D115. doi:10.1093/nar/gkv1176
He ZY, Shi CB, Wen H, Li FL, Wang BL, Wang J (2011) Upregulation of p53 expression in patients with colorectal cancer by administration of curcumin. Cancer Invest 29(3):208–213. doi:10.3109/07357907.2010.550592
Fu SQ, Kurzrock R (2010) Development of curcumin as an epigenetic agent. Cancer Am Cancer Soc 116 (20):4670–4676. doi:10.1002/cncr.25414
Bao B, Ali S, Banerjee S, Wang ZW, Logna F, Azmi AS, Kong DJ, Ahmad A, Li YW, Padhye S, Sarkar FH (2012) Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res 72(1):335–345. doi:10.1158/0008-5472.CAN-11-2182
Bryant RJ, Pawlowski T, Catto JWF, Marsden G, Vessella RL, Rhees B, Kuslich C, Visakorpi T, Hamdy FC (2012) Changes in circulating microRNA levels associated with prostate cancer. Br J Cancer 106(4):768–774. doi:10.1038/bjc.2011.595
Ozen M, Creighton CJ, Ozdemir M, Ittmann M (2008) Widespread deregulation of microRNA expression in human prostate cancer. Oncogene 27(12):1788–1793. doi:10.1038/sj.onc.1210809
Slaby O, Svoboda M, Fabian P, Smerdova T, Knoflickova D, Bednarikova M, Nenutil R, Vyzula R (2007) Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology-Basel 72(5–6):397–402. doi:10.1159/000113489
Gao W, Yu Y, Cao H, Shen H, Li X, Pan S, Shu Y (2010) Deregulated expression of miR-21, miR-143 and miR-181a in non small cell lung cancer is related to clinicopathologic characteristics or patient prognosis. Biomed Pharmacother 64(6):399–408
Jiang S, Zhang LF, Zhang HW, Hu S, Lu MH, Liang S, Li B, Li Y, Li DS, Wang ED, Liu MF (2012) A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells. Embo J 31(8):1985–1998. doi:10.1038/emboj.2012.45
Clape C, Fritz V, Henriquet C, Apparailly F, Fernandez PL, Iborra F, Avances C, Villalba M, Culine S, Fajas L (2009) miR-143 Interferes with ERK5 signaling, and abrogates prostate cancer progression in mice. Plos One 4(10). doi:ARTN e754210.1371/journal.pone.0007542
Bin X (2012) Mir-143 decreases prostate cancer cells proliferation and migration and enhances their sensitivity to docetaxel through suppression of kras. Int J Urol 19:197–197
Hu H, Zhu W, Qin J, Chen M, Gong L, Li L, Liu X, Tao Y, Yin H, Zhou H (2017) Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis. Hepatology 65(2):515–528
Ameis HM, Drenckhan A, von Loga K, Escherich G, Wenke K, Izbicki JR, Reinshagen K, Gros SJ (2013) PGK1 as predictor of CXCR4 expression, bone marrow metastases and survival in neuroblastoma. Plos One 8(12):e83701
Li X, Jiang Y, Meisenhelder J, Yang W, Hawke DH, Zheng Y, Xia Y, Aldape K, He J, Hunter T (2016) Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis. Mol Cell 61(5):705–719
Schneider CC, Archid R, Fischer N, Bühler S, Venturelli S, Berger A, Burkard M, Kirschniak A, Bachmann R, Königsrainer A (2015) Metabolic alteration–Overcoming therapy resistance in gastric cancer via PGK-1 inhibition in a combined therapy with standard chemotherapeutics. Int J Surg 22:92–98
Wang J, Ying G, Wang J, Jung Y, Lu J, Zhu J, Pienta KJ, Taichman RS (2010) Characterization of phosphoglycerate kinase-1 expression of stromal cells derived from tumor microenvironment in prostate cancer progression. Cancer Res 70(2):471–480
Romanuik TL, Ueda T, Le N, Haile S, Yong TM, Thomson T, Vessella RL, Sadar MD (2009) Novel biomarkers for prostate cancer including noncoding transcripts. Am J Pathol 175(6):2264–2276
Liu LL, Lu SX, Li M, Li LZ, Fu J, Hu W, Yang YZ, Luo RZ, Zhang CZ, Yun JP (2014) FoxD3-regulated microRNA-137 suppresses tumour growth and metastasis in human hepatocellular carcinoma by targeting AKT2. Oncotarget 5(13):5113–5124. doi:10.18632/oncotarget.2089
He G, Hu J, Zhou L, Zhu X, Xin S, Zhang D, Lu G, Liao W, Ding Y, Liang L (2016) The FOXD3/miR-214/MED19 axis suppresses tumour growth and metastasis in human colorectal cancer. Br J Cancer 115(11):1367–1378
Elia L, Quintavalle M, Zhang J, Contu R, Cossu L, Latronico MV, Peterson KL, Indolfi C, Catalucci D, Chen J (2009) The knockout of miR-143 and-145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Diff 16(12):1590–1598
This study was supported by Project for Key Disease Type of Chinese and Western Integrative Medicine, Shanghai Municipal Commission of Heath and Family Planning: Special Subject Construction of Treating Prostatic Cancer by Chinese and Western Integrative Medicine (Subject Number: ZXBZ2012-07); Project of Establishing Working Studio of Shanghai Doctor of Traditional Chinese Medicine, Zhou Zhiheng (Subject Number: ZYSNXD-CC-MZY011); The three year plan of Shanghai to further accelerate the development of traditional Chinese Medicine (No: ZY3-RCPY-3-1012). We thank Shanghai Doctor of Traditional Chinese Medicine, Professor Zhiheng Zhou for his help.
HWC, HJY, and YGF carried out the experiments, participated in the statistical analysis, and drafted the manuscript; FL and LC conceived of the study, and participated in its design and coordination, and helped to draft the manuscript.
Conflict of interest
The authors declare that there is no conflict of interests.
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
This study was supported by Project for Key Disease Type of Chinese and Western Integrative Medicine, Shanghai Municipal Commission of Heath and Family Planning: Special Subject Construction of Treating Prostatic Cancer by Chinese and Western Integrative Medicine (Subject Number: ZXBZ2012-07); Project of Establishing Working Studio of Shanghai Doctor of Traditional Chinese Medicine, Zhou Zhiheng (Subject Number: ZYSNXD-CC-MZY011); The three year plan of Shanghai to further accelerate the development of traditional Chinese Medicine (No: ZY3-RCPY-3-1012).
Hongwen Cao, Hongjie Yu, and Yigeng Feng contributed equally.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Cao, H., Yu, H., Feng, Y. et al. Curcumin inhibits prostate cancer by targeting PGK1 in the FOXD3/miR-143 axis. Cancer Chemother Pharmacol 79, 985–994 (2017). https://doi.org/10.1007/s00280-017-3301-1