Abstract
Purpose
Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, the investigation about the molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The objective of the present study is to investigate the effects of valproic acid (VPA), a histone deacetylase inhibitor, on the angiogenesis of cervical cancer.
Methods
The effects and mechanisms of VPA on in vitro angiogenesis and vascular endothelial growth factor (VEGF) expression of human cervical cancer HeLa and SiHa cells were investigated.
Results
Our present study reveals that 1 mM VPA can significantly inhibit the in vitro angiogenic potential and VEGF expression of human cervical cancer HeLa and SiHa cells. Further, the transcription and protein levels of hypoxia inducible factor-1α (HIF-1α), and not HIF-1β, are significantly inhibited in VPA-treated cervical cancer cells. Over expression of HIF-1α can obviously reverse VPA-induced VEGF down regulation. VPA-treatment decreases the activation of Akt and ERK1/2 in both HeLa and SiHa cells in a time-dependent manner. The inhibitor of Akt (LY 294002) or ERK1/2 (PD98059) can inhibit VEGF alone and cooperatively reinforce the suppression effects of VPA on HIF-1α and VEGF expression.
Conclusion
Collectively, our data reveal that the inhibition of PI3K/Akt and ERK1/2 signals are involved in VPA-induced HIF-1α and VEGF suppression of cervical cancer cells.
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References
Arbyn M, Castellsague X, de Sanjose S, Bruni L, Saraiya M, Bray F, et al. Worldwide burden of cervical cancer in 2008. Ann Oncol. 2011;22:2675–86.
Maestri D, Reis RJ, Bacha OM, Muller B, Corleta OC. A comparison of radical vaginal hysterectomy combined with extraperitoneal or laparoscopic pelvic lymphadenectomy in the treatment of cervical cancer. Int J Gynecol Cancer. 2012;22:1238–43.
Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–92.
Baylin SB, Jones PA. A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer. 2011;11:726–34.
Zhang J, Zhong Q. Histone deacetylase inhibitors and cell death. Cell Mol Life Sci. 2014;71:3885–901.
van Breemen MS, Rijsman RM, Taphoorn MJ, Walchenbach R, Zwinkels H, Vecht CJ. Efficacy of anti-epileptic drugs in patients with gliomas and seizures. J Neurol. 2009;256:1519–26.
Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20:6969–78.
Liu X, Chen L, Sun F, Zhang G. Enhanced suppression of proliferation and migration in highly-metastatic lung cancer cells by combination of valproic acid and coumarin-3-carboxylic acid and its molecular mechanisms of action. Cytotechnology. 2013;65:597–608.
Yang FQ, Liu M, Yang FP, Che J, Li W, Zhai W, et al. VPA inhibits renal cancer cell migration by targeting HDAC2 and down-regulating HIF-1alpha. Mol Biol Rep. 2014;41:1511–8.
Wang D, Jing Y, Ouyang S, Liu B, Zhu T, Niu H, et al. Inhibitory effect of valproic acid on bladder cancer in combination with chemotherapeutic agents in vitro and in vivo. Oncol Lett. 2013;6:1492–8.
Moreaux J, Reme T, Leonard W, Veyrune JL, Requirand G, Goldschmidt H, et al. Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors. Br J Cancer. 2013;109:676–85.
Ellis L, Hammers H, Pili R. Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer Lett. 2009;280:145–53.
Lin EY, Pollard JW. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 2007;67:5064–6.
Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A, Clausse N, et al. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene. 2002;21:427–36.
Kwon HJ, Kim MS, Kim MJ, Nakajima H, Kim KW. Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer. 2002;97:290–6.
Shan Z, Feng-Nian R, Jie G, Ting Z. Effects of valproic acid on proliferation, apoptosis, angiogenesis and metastasis of ovarian cancer in vitro and in vivo. Asian Pac J Cancer Prev. 2012;13:3977–82.
Osuka S, Takano S, Yamamoto T, Ishikawa E, Matsumura A. Histone deacetylase inhibitor, valproic acid inhibits glioma angiogenesis in vitro and in vivo in the brain. Neuro-oncol. 2009;11:962.
Zhang ZH, Hao CL, Liu P, Tian X, Wang LH, Zhao L, et al. Valproic acid inhibits tumor angiogenesis in mice transplanted with Kasumi1 leukemia cells. Mol Med Rep. 2013;9:443–9.
Ge LC, Chen ZJ, Liu HY, Zhang KS, Liu H, Huang HB, et al. Involvement of activating ERK1/2 through G protein coupled receptor 30 and estrogen receptor alpha/beta in low doses of bisphenol A promoting growth of Sertoli TM4 cells. Toxicol Lett. 2014;226:81–9.
Fang J, Xia C, Cao Z, Zheng JZ, Reed E, Jiang BH. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 2005;19:342–53.
Mawatari T, Ninomiya I, Inokuchi M, Harada S, Hayashi H, Oyama K, et al. Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation. Int J Oncol. 2015;47:2073–81.
Sami S, Hoti N, Xu HM, Shen ZL, Huang XF. Valproic acid inhibits the growth of cervical cancer both in vitro and in vivo. J Biochem (Tokyo). 2008;144:357–62.
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16:4604–13.
Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem. 1996;271:17771–8.
Blancher C, Moore JW, Robertson N, Harris AL. Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3′-kinase/Akt signaling pathway. Cancer Res. 2001;61:7349–55.
Shen K, Ji L, Gong C, Ma Y, Yang L, Fan Y, et al. Notoginsenoside Ft1 promotes angiogenesis via HIF-1alpha mediated VEGF secretion and the regulation of PI3K/AKT and Raf/MEK/ERK signaling pathways. Biochem Pharmacol. 2012;84:784–92.
Das CM, Aguilera D, Vasquez H, Prasad P, Zhang M, Wolff JE, et al. Valproic acid induces p21 and topoisomerase-II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines. J Neurooncol. 2007;85:159–70.
Byler TK, Leocadio D, Shapiro O, Bratslavsky G, Stodgell CJ, Wood RW, et al. Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression. BMC Urol. 2012;12:21.
Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110:2302–8.
Michaelis M, Michaelis UR, Fleming I, Suhan T, Cinatl J, Blaheta RA, et al. Valproic acid inhibits angiogenesis in vitro and in vivo. Mol Pharmacol. 2004;65:520–7.
Isenberg JS, Jia Y, Field L, Ridnour LA, Sparatore A, Del Soldato P, et al. Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid. Br J Pharmacol. 2007;151:63–72.
Zgouras D, Becker U, Loitsch S, Stein J. Modulation of angiogenesis-related protein synthesis by valproic acid. Biochem Biophys Res Commun. 2004;316:693–7.
Gao D, Xia Q, Lv J, Zhang H. Chronic administration of valproic acid inhibits PC3 cell growth by suppressing tumor angiogenesis in vivo. Int J Urol. 2007;14:838–45.
Kitazoe K, Abe M, Hiasa M, Oda A, Amou H, Harada T, et al. Valproic acid exerts anti-tumor as well as anti-angiogenic effects on myeloma. Int J Hematol. 2009;89:45–57.
Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med. 2001;7:437–43.
Luo HM, Du MH, Lin ZL, Zhang L, Ma L, Wang H, et al. Valproic acid treatment inhibits hypoxia-inducible factor 1alpha accumulation and protects against burn-induced gut barrier dysfunction in a rodent model. PLoS One. 2013;8:e77523.
Chen SY, Sang NL. Histone deacetylase inhibitors: the epigenetic therapeutics that repress hypoxia-inducible factors. J Biomed Biotechnol. 2011;2011:197946.
Wang JH, Wang JC, Sun YX, Song WY, Nor JE, Wang CY, et al. Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis. Cell Signal. 2005;17:1578–92.
Zhou CL, Yu XJ, Chen LM, Jiang H, Li CY. Corticotropin-releasing hormone attenuates vascular endothelial growth factor release from human HaCaT keratinocytes. Regul Pept. 2010;160:115–20.
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Zhao, Y., You, W., Zheng, J. et al. Valproic acid inhibits the angiogenic potential of cervical cancer cells via HIF-1α/VEGF signals. Clin Transl Oncol 18, 1123–1130 (2016). https://doi.org/10.1007/s12094-016-1494-0
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DOI: https://doi.org/10.1007/s12094-016-1494-0