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Published in: Tumor Biology 12/2016

01-12-2016 | Original Article

Norcantharidin induces autophagy-related prostate cancer cell death through Beclin-1 upregulation by miR-129-5p suppression

Authors: Wenjun Xiao, Bo Dai, Yao Zhu, Dingwei Ye

Published in: Tumor Biology | Issue 12/2016

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Abstract

Norcantharidin (NCTD) has an anticancer potential to allow it to be used in the treatment of some malignant cancers. However, whether NCTD may have similar anticancer effects on prostate cancer (PC) is unknown. Here, we aimed to examine the effects of NCTD on PC cells and the underlying mechanisms. We found that NCTD dose-dependently inhibited the PC cell growth, in either a cell counting kit-8 (CCK-8) assay or a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Moreover, NCTD dose-dependently increased the PC cell autophagy, through upregulation of Beclin-1. Furthermore, the Beclin-1 protein, but not mRNA, was regulated by NCTD in PC cells, suggesting post-transcriptional control of Beclin-1 by NCTD. Finally, microRNA (miR)-129-5p was found to be regulated by NCTD, and bioinformatics analyses showed that miR-129-5p targeted the 3′-UTR of Beclin-1 mRNA to inhibit its translation, which was confirmed by luciferase reporter assay. Together, these data suggest that NCTD may upregulate Beclin-1 through suppression of miR-129-5p to induce autophagic cell death and cell proliferation arrest in PC cells. Our study sheds light on using NCTD as a novel treatment for PC.
Literature
1.
go back to reference Dhar S, Kolishetti N, Lippard SJ, Farokhzad OC. Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo. Proc Natl Acad Sci U S A. 2011;108:1850–5.CrossRefPubMedPubMedCentral Dhar S, Kolishetti N, Lippard SJ, Farokhzad OC. Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo. Proc Natl Acad Sci U S A. 2011;108:1850–5.CrossRefPubMedPubMedCentral
2.
go back to reference Villar J, Quadri HS, Song I, Tomita Y, Tirado OM, Notario V. PCPH/ENTPD5 expression confers to prostate cancer cells resistance against cisplatin-induced apoptosis through protein kinase calpha-mediated Bcl-2 stabilization. Cancer Res. 2009;69:102–10.CrossRefPubMedPubMedCentral Villar J, Quadri HS, Song I, Tomita Y, Tirado OM, Notario V. PCPH/ENTPD5 expression confers to prostate cancer cells resistance against cisplatin-induced apoptosis through protein kinase calpha-mediated Bcl-2 stabilization. Cancer Res. 2009;69:102–10.CrossRefPubMedPubMedCentral
3.
go back to reference Dhar S, Gu FX, Langer R, Farokhzad OC, Lippard SJ. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc Natl Acad Sci U S A. 2008;105:17356–61.CrossRefPubMedPubMedCentral Dhar S, Gu FX, Langer R, Farokhzad OC, Lippard SJ. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc Natl Acad Sci U S A. 2008;105:17356–61.CrossRefPubMedPubMedCentral
4.
go back to reference Kok SH, Hong CY, Kuo MY, Lee CH, Lee JJ, Lou IU, et al. Comparisons of norcantharidin cytotoxic effects on oral cancer cells and normal buccal keratinocytes. Oral Oncol. 2003;39:19–26.CrossRefPubMed Kok SH, Hong CY, Kuo MY, Lee CH, Lee JJ, Lou IU, et al. Comparisons of norcantharidin cytotoxic effects on oral cancer cells and normal buccal keratinocytes. Oral Oncol. 2003;39:19–26.CrossRefPubMed
5.
go back to reference Wang X, Gu Z, Li G, Zhang S, Cao Z, Yang Z, et al. Norcantharidin enhances ABT-263-mediated anticancer activity in neuroblastoma cells by upregulation of noxa. Oncol Rep. 2014;32:716–22.PubMed Wang X, Gu Z, Li G, Zhang S, Cao Z, Yang Z, et al. Norcantharidin enhances ABT-263-mediated anticancer activity in neuroblastoma cells by upregulation of noxa. Oncol Rep. 2014;32:716–22.PubMed
6.
go back to reference Shou LM, Zhang QY, Li W, Xie X, Chen K, Lian L, et al. Cantharidin and norcantharidin inhibit the ability of MCF-7 cells to adhere to platelets via protein kinase C pathway-dependent downregulation of alpha2 integrin. Oncol Rep. 2013;30:1059–66.PubMedPubMedCentral Shou LM, Zhang QY, Li W, Xie X, Chen K, Lian L, et al. Cantharidin and norcantharidin inhibit the ability of MCF-7 cells to adhere to platelets via protein kinase C pathway-dependent downregulation of alpha2 integrin. Oncol Rep. 2013;30:1059–66.PubMedPubMedCentral
7.
go back to reference Lee YC, Lee LM, Yang CH, Lin AM, Huang YC, Hsu CC, et al. Norcantharidin suppresses cell growth and migration with enhanced anticancer activity of gefitinib and cisplatin in human non-small cell lung cancer cells. Oncol Rep. 2013;29:237–43.PubMed Lee YC, Lee LM, Yang CH, Lin AM, Huang YC, Hsu CC, et al. Norcantharidin suppresses cell growth and migration with enhanced anticancer activity of gefitinib and cisplatin in human non-small cell lung cancer cells. Oncol Rep. 2013;29:237–43.PubMed
8.
go back to reference Xie X, Wu MY, Shou LM, Chen LP, Gong FR, Chen K, et al. Tamoxifen enhances the anticancer effect of cantharidin and norcantharidin in pancreatic cancer cell lines through inhibition of the protein kinase c signaling pathway. Oncology letters. 2015;9:837–44.PubMed Xie X, Wu MY, Shou LM, Chen LP, Gong FR, Chen K, et al. Tamoxifen enhances the anticancer effect of cantharidin and norcantharidin in pancreatic cancer cell lines through inhibition of the protein kinase c signaling pathway. Oncology letters. 2015;9:837–44.PubMed
9.
go back to reference Xie J, Zhang Y, Hu X, Lv R, Xiao D, Jiang L, et al. Norcantharidin inhibits wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer. Med Oncol. 2015;32:145.CrossRefPubMed Xie J, Zhang Y, Hu X, Lv R, Xiao D, Jiang L, et al. Norcantharidin inhibits wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer. Med Oncol. 2015;32:145.CrossRefPubMed
10.
go back to reference Chen YJ, Tsai YM, Kuo CD, Ku KL, Shie HS, Liao HF. Norcantharidin is a small-molecule synthetic compound with anti-angiogenesis effect. Life Sci. 2009;85:642–51.CrossRefPubMed Chen YJ, Tsai YM, Kuo CD, Ku KL, Shie HS, Liao HF. Norcantharidin is a small-molecule synthetic compound with anti-angiogenesis effect. Life Sci. 2009;85:642–51.CrossRefPubMed
11.
go back to reference Zhu W, Sun W, Zhang JT, Liu ZY, Li XP, Fan YZ. Norcantharidin enhances TIMP2 antivasculogenic mimicry activity for human gallbladder cancers through downregulating MMP2 and MT1MMP. Int J Oncol. 2015;46:627–40.PubMed Zhu W, Sun W, Zhang JT, Liu ZY, Li XP, Fan YZ. Norcantharidin enhances TIMP2 antivasculogenic mimicry activity for human gallbladder cancers through downregulating MMP2 and MT1MMP. Int J Oncol. 2015;46:627–40.PubMed
12.
go back to reference Zhang JT, Fan YZ, Chen CQ, Zhao ZM, Sun W. Norcantharidin: a potential antiangiogenic agent for gallbladder cancers in vitro and in vivo. Int J Oncol. 2012;40:1501–14.PubMed Zhang JT, Fan YZ, Chen CQ, Zhao ZM, Sun W. Norcantharidin: a potential antiangiogenic agent for gallbladder cancers in vitro and in vivo. Int J Oncol. 2012;40:1501–14.PubMed
13.
go back to reference Zhang S, Li G, Ma X, Wang Y, Liu G, Feng L, et al. Norcantharidin enhances ABT-737-induced apoptosis in hepatocellular carcinoma cells by transcriptional repression of MCL-1. Cell Signal. 2012;24:1803–9.CrossRefPubMed Zhang S, Li G, Ma X, Wang Y, Liu G, Feng L, et al. Norcantharidin enhances ABT-737-induced apoptosis in hepatocellular carcinoma cells by transcriptional repression of MCL-1. Cell Signal. 2012;24:1803–9.CrossRefPubMed
14.
go back to reference Zhang JT, Sun W, Zhang WZ, Ge CY, Liu ZY, Zhao ZM, et al. Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPS/Ln-5gamma2 signaling pathway. BMC Cancer. 2014;14:193.CrossRefPubMedPubMedCentral Zhang JT, Sun W, Zhang WZ, Ge CY, Liu ZY, Zhao ZM, et al. Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPS/Ln-5gamma2 signaling pathway. BMC Cancer. 2014;14:193.CrossRefPubMedPubMedCentral
15.
go back to reference Li XP, Jing W, Sun JJ, Liu ZY, Zhang JT, Sun W, et al. A potential small-molecule synthetic antilymphangiogenic agent norcantharidin inhibits tumor growth and lymphangiogenesis of human colonic adenocarcinomas through blocking VEGF-A,-C,-D/VEGFR-2,-3 “multi-points priming” mechanisms in vitro and in vivo. BMC Cancer. 2015;15:527.CrossRefPubMedPubMedCentral Li XP, Jing W, Sun JJ, Liu ZY, Zhang JT, Sun W, et al. A potential small-molecule synthetic antilymphangiogenic agent norcantharidin inhibits tumor growth and lymphangiogenesis of human colonic adenocarcinomas through blocking VEGF-A,-C,-D/VEGFR-2,-3 “multi-points priming” mechanisms in vitro and in vivo. BMC Cancer. 2015;15:527.CrossRefPubMedPubMedCentral
20.
go back to reference Huang CY, Huang SP, Lin VC, Yu CC, Chang TY, Lu TL, et al. Genetic variants of the autophagy pathway as prognostic indicators for prostate cancer. Sci Rep. 2015;5:14045.CrossRefPubMedPubMedCentral Huang CY, Huang SP, Lin VC, Yu CC, Chang TY, Lu TL, et al. Genetic variants of the autophagy pathway as prognostic indicators for prostate cancer. Sci Rep. 2015;5:14045.CrossRefPubMedPubMedCentral
22.
go back to reference Shi Y, Han JJ, Tennakoon JB, Mehta FF, Merchant FA, Burns AR, et al. Androgens promote prostate cancer cell growth through induction of autophagy. Mol Endocrinol. 2013;27:280–95.CrossRefPubMed Shi Y, Han JJ, Tennakoon JB, Mehta FF, Merchant FA, Burns AR, et al. Androgens promote prostate cancer cell growth through induction of autophagy. Mol Endocrinol. 2013;27:280–95.CrossRefPubMed
23.
go back to reference Ouyang DY, Xu LH, He XH, Zhang YT, Zeng LH, Cai JY, et al. Autophagy is differentially induced in prostate cancer LNCaP, DU145 and PC-3 cells via distinct splicing profiles of ATG5. Autophagy. 2013;9:20–32.CrossRefPubMedPubMedCentral Ouyang DY, Xu LH, He XH, Zhang YT, Zeng LH, Cai JY, et al. Autophagy is differentially induced in prostate cancer LNCaP, DU145 and PC-3 cells via distinct splicing profiles of ATG5. Autophagy. 2013;9:20–32.CrossRefPubMedPubMedCentral
24.
go back to reference Lian J, Karnak D, Xu L. The Bcl-2-Beclin 1 interaction in (−)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Autophagy. 2010;6:1201–3.CrossRefPubMedPubMedCentral Lian J, Karnak D, Xu L. The Bcl-2-Beclin 1 interaction in (−)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Autophagy. 2010;6:1201–3.CrossRefPubMedPubMedCentral
26.
go back to reference Lin R, Feng J, Dong S, Pan R, Zhuang H, Ding Z. Regulation of autophagy of prostate cancer cells by beta-catenin signaling. Cell Physiol Biochem. 2015;35:926–32.CrossRefPubMed Lin R, Feng J, Dong S, Pan R, Zhuang H, Ding Z. Regulation of autophagy of prostate cancer cells by beta-catenin signaling. Cell Physiol Biochem. 2015;35:926–32.CrossRefPubMed
27.
go back to reference Sun R, Luo Y, Li J, Wang Q, Li J, Chen X, et al. Ammonium chloride inhibits autophagy of hepatocellular carcinoma cells through SMAD2 signaling. Tumour Biol. 2015;36:1173–7.CrossRefPubMed Sun R, Luo Y, Li J, Wang Q, Li J, Chen X, et al. Ammonium chloride inhibits autophagy of hepatocellular carcinoma cells through SMAD2 signaling. Tumour Biol. 2015;36:1173–7.CrossRefPubMed
28.
go back to reference Mei Q, Li F, Quan H, Liu Y, Xu H. Busulfan inhibits growth of human osteosarcoma through miR-200 family microRNAs in vitro and in vivo. Cancer Sci. 2014;105:755–62.CrossRefPubMedPubMedCentral Mei Q, Li F, Quan H, Liu Y, Xu H. Busulfan inhibits growth of human osteosarcoma through miR-200 family microRNAs in vitro and in vivo. Cancer Sci. 2014;105:755–62.CrossRefPubMedPubMedCentral
29.
go back to reference Chang Y, Zhao Y, Gu W, Cao Y, Wang S, Pang J, et al. Bufalin inhibits the differentiation and proliferation of cancer stem cells derived from primary osteosarcoma cells through miR-148a. Cell Physiol Biochem. 2015;36:1186–96.CrossRefPubMed Chang Y, Zhao Y, Gu W, Cao Y, Wang S, Pang J, et al. Bufalin inhibits the differentiation and proliferation of cancer stem cells derived from primary osteosarcoma cells through miR-148a. Cell Physiol Biochem. 2015;36:1186–96.CrossRefPubMed
30.
go back to reference Song W, Li Q, Wang L, Wang L. Modulation of FOXO1 expression by miR-21 to promote growth of pancreatic ductal adenocarcinoma. Cell Physiol Biochem. 2015;35:184–90.CrossRefPubMed Song W, Li Q, Wang L, Wang L. Modulation of FOXO1 expression by miR-21 to promote growth of pancreatic ductal adenocarcinoma. Cell Physiol Biochem. 2015;35:184–90.CrossRefPubMed
31.
go back to reference Jin Y, Lu J, Wen J, Shen Y, Wen X. Regulation of growth of human bladder cancer by miR-192. Tumour Biol. 2015;36:3791–7.CrossRefPubMed Jin Y, Lu J, Wen J, Shen Y, Wen X. Regulation of growth of human bladder cancer by miR-192. Tumour Biol. 2015;36:3791–7.CrossRefPubMed
32.
go back to reference Wang Q, Cai J, Wang J, Xiong C, Zhao J. miR-143 inhibits EGFR-signaling-dependent osteosarcoma invasion. Tumour Biol. 2014;35:12743–8.CrossRefPubMed Wang Q, Cai J, Wang J, Xiong C, Zhao J. miR-143 inhibits EGFR-signaling-dependent osteosarcoma invasion. Tumour Biol. 2014;35:12743–8.CrossRefPubMed
33.
go back to reference Liu G, Jiang C, Li D, Wang R, Wang W. miRNA-34a inhibits EGFR-signaling-dependent MMP7 activation in gastric cancer. Tumour Biol. 2014;35:9801–6.CrossRefPubMed Liu G, Jiang C, Li D, Wang R, Wang W. miRNA-34a inhibits EGFR-signaling-dependent MMP7 activation in gastric cancer. Tumour Biol. 2014;35:9801–6.CrossRefPubMed
34.
go back to reference Wang F, Xiao W, Sun J, Han D, Zhu Y. miRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma. Tumour Biol. 2014;35:8653–8.CrossRefPubMed Wang F, Xiao W, Sun J, Han D, Zhu Y. miRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma. Tumour Biol. 2014;35:8653–8.CrossRefPubMed
35.
go back to reference Huang SQ, Liao QJ, Wang XW, Xin DQ, Chen SX, Wu QJ, et al. RNAi-mediated knockdown of pituitary tumor- transforming gene-1 (PTTG1) suppresses the proliferation and invasive potential of PC3 human prostate cancer cells. Braz J Med Biol Res. 2012;45:995–1001.CrossRefPubMedPubMedCentral Huang SQ, Liao QJ, Wang XW, Xin DQ, Chen SX, Wu QJ, et al. RNAi-mediated knockdown of pituitary tumor- transforming gene-1 (PTTG1) suppresses the proliferation and invasive potential of PC3 human prostate cancer cells. Braz J Med Biol Res. 2012;45:995–1001.CrossRefPubMedPubMedCentral
37.
go back to reference Brest P, Lassalle S, Hofman V, Bordone O, Gavric Tanga V, Bonnetaud C, et al. miR-129-5p is required for histone deacetylase inhibitor-induced cell death in thyroid cancer cells. Endocr Relat Cancer. 2011;18:711–9.CrossRefPubMed Brest P, Lassalle S, Hofman V, Bordone O, Gavric Tanga V, Bonnetaud C, et al. miR-129-5p is required for histone deacetylase inhibitor-induced cell death in thyroid cancer cells. Endocr Relat Cancer. 2011;18:711–9.CrossRefPubMed
38.
go back to reference Duan L, Hao X, Liu Z, Zhang Y, Zhang G. miR-129-5p is down-regulated and involved in the growth, apoptosis and migration of medullary thyroid carcinoma cells through targeting RET. FEBS Lett. 2014;588:1644–51.CrossRefPubMed Duan L, Hao X, Liu Z, Zhang Y, Zhang G. miR-129-5p is down-regulated and involved in the growth, apoptosis and migration of medullary thyroid carcinoma cells through targeting RET. FEBS Lett. 2014;588:1644–51.CrossRefPubMed
39.
go back to reference Li M, Tian L, Wang L, Yao H, Zhang J, Lu J, et al. Down-regulation of miR-129-5p inhibits growth and induces apoptosis in laryngeal squamous cell carcinoma by targeting APC. PLoS One. 2013;8, e77829.CrossRefPubMedPubMedCentral Li M, Tian L, Wang L, Yao H, Zhang J, Lu J, et al. Down-regulation of miR-129-5p inhibits growth and induces apoptosis in laryngeal squamous cell carcinoma by targeting APC. PLoS One. 2013;8, e77829.CrossRefPubMedPubMedCentral
40.
go back to reference Dossing KB, Binderup T, Kaczkowski B, Jacobsen A, Rossing M, Winther O, et al. Down-regulation of miR-129-5p and the let-7 family in neuroendocrine tumors and metastases leads to up-regulation of their targets Egr1, G3bp1, Hmga2 and Bach1. Genes (Basel). 2014;6:1–21. Dossing KB, Binderup T, Kaczkowski B, Jacobsen A, Rossing M, Winther O, et al. Down-regulation of miR-129-5p and the let-7 family in neuroendocrine tumors and metastases leads to up-regulation of their targets Egr1, G3bp1, Hmga2 and Bach1. Genes (Basel). 2014;6:1–21.
41.
go back to reference Long XH, Zhou YF, Peng AF, Zhang ZH, Chen XY, Chen WZ, et al. Demethylation-mediated miR-129-5p up-regulation inhibits malignant phenotype of osteogenic osteosarcoma by targeting Homo sapiens valosin-containing protein (VCP). Tumour Biol. 2015;36:3799–806.CrossRefPubMed Long XH, Zhou YF, Peng AF, Zhang ZH, Chen XY, Chen WZ, et al. Demethylation-mediated miR-129-5p up-regulation inhibits malignant phenotype of osteogenic osteosarcoma by targeting Homo sapiens valosin-containing protein (VCP). Tumour Biol. 2015;36:3799–806.CrossRefPubMed
Metadata
Title
Norcantharidin induces autophagy-related prostate cancer cell death through Beclin-1 upregulation by miR-129-5p suppression
Authors
Wenjun Xiao
Bo Dai
Yao Zhu
Dingwei Ye
Publication date
01-12-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4488-6

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