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Published in: Journal of Cancer Research and Clinical Oncology 5/2014

01-05-2014 | Original Article - Cancer Research

Resveratrol plays dual roles in pancreatic cancer cells

Authors: Lei Yang, Liang Yang, Wencong Tian, Jing Li, Jie Liu, Mengmeng Zhu, Yan Zhang, Yinan Yang, Fei Liu, Qiong Zhang, Qianqian Liu, Yanna Shen, Zhi Qi

Published in: Journal of Cancer Research and Clinical Oncology | Issue 5/2014

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Abstract

Purpose

Although the potential anticancer effect of resveratrol (RSV) on pancreatic cancer has been reported, its mechanism was not fully understood. The role of vascular endothelial growth factor B (VEGF-B) in cancer remains controversial. Herein, we aimed to examine whether the anticancer effect of RSV was related to the VEGF-B.

Methods

The effect of RSV on pancreatic cancer cell line (capan-2 cells) was evaluated by CCK-8 assay, Hoechst 33342 staining, and flow cytometry. The mRNA level of VEGF-B was measured by real-time PCR. VEGF-B expression was knockdown by small interfering RNA (siRNA).The protein levels of VEGF-B, glycogen synthase kinase-3 beta (GSK-3β), and Bax were measured by Western blot.

Results

Resveratrol treatment inhibited tumor growth, induced apoptosis, and up-regulated Bax expression in capan-2 cells. The mRNA and protein levels of VEGF-B were up-regulated after RSV treatment. However, VEGF-B siRNA treatment increased the apoptotic rate, and inhibited tumor activator GSK-3β, while Bax expression was not affected. The combination of RSV and VEGF-B siRNA showed significantly higher apoptotic rate in comparison with RSV or VEGF-B siRNA mono-treatment group.

Conclusions

Resveratrol plays dual roles in pancreatic cancer: as a tumor suppressor via the up-regulation of Bax; as a tumor activator via the up-regulation of VEGF-B; and the anticancer effect of RSV is much stronger than the cancer promotion effect. The combination of RSV with pharmacological inhibitor of VEGF-B might, therefore, be a promising modality for clinical pancreatic cancer therapy.
Literature
go back to reference Albrecht I, Kopfstein L, Strittmatter K, Schomber T, Falkevall A, Hagberg CE, Lorentz P, Jeltsch M, Alitalo K, Eriksson U (2010) Suppressive effects of vascular endothelial growth factor-B on tumor growth in a mouse model of pancreatic neuroendocrine tumorigenesis. PLoS ONE 5:e14109CrossRefPubMedPubMedCentral Albrecht I, Kopfstein L, Strittmatter K, Schomber T, Falkevall A, Hagberg CE, Lorentz P, Jeltsch M, Alitalo K, Eriksson U (2010) Suppressive effects of vascular endothelial growth factor-B on tumor growth in a mouse model of pancreatic neuroendocrine tumorigenesis. PLoS ONE 5:e14109CrossRefPubMedPubMedCentral
go back to reference Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L (2007) Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev 128:546–552CrossRefPubMed Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L (2007) Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev 128:546–552CrossRefPubMed
go back to reference Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506CrossRefPubMed Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506CrossRefPubMed
go back to reference Castillo-Pichardo L, Cubano LA, Dharmawardhane S (2013) Dietary grape polyphenol resveratrol increases mammary tumor growth and metastasis in immunocompromised mice. BMC Complement Altern Med 13:6CrossRefPubMedPubMedCentral Castillo-Pichardo L, Cubano LA, Dharmawardhane S (2013) Dietary grape polyphenol resveratrol increases mammary tumor growth and metastasis in immunocompromised mice. BMC Complement Altern Med 13:6CrossRefPubMedPubMedCentral
go back to reference Chen CJ, Fu YC, Yu W, Wang W (2013) SIRT3 protects cardiomyocytes from oxidative stress-mediated cell death by activating NF-κB. Biochem Biophys Res Commun 430:798–803CrossRefPubMed Chen CJ, Fu YC, Yu W, Wang W (2013) SIRT3 protects cardiomyocytes from oxidative stress-mediated cell death by activating NF-κB. Biochem Biophys Res Commun 430:798–803CrossRefPubMed
go back to reference Cho IR, Koh SS, Malilas W, Srisuttee R, Moon J, Choi YW, Horio Y, Oh S, Chung YH (2012) SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of β-catenin. Biochem Biophys Res Commun 423:270–275CrossRefPubMed Cho IR, Koh SS, Malilas W, Srisuttee R, Moon J, Choi YW, Horio Y, Oh S, Chung YH (2012) SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of β-catenin. Biochem Biophys Res Commun 423:270–275CrossRefPubMed
go back to reference Do GM, Kwon EY, Kim HJ, Jeon SM, Ha TY, Park T, Choi MS (2008) Long-term effects of resveratrol supplementation on suppression of atherogenic lesion formation and cholesterol synthesis in apo E-deficient mice. Biochem Biophys Res Commun 374:55–59CrossRefPubMed Do GM, Kwon EY, Kim HJ, Jeon SM, Ha TY, Park T, Choi MS (2008) Long-term effects of resveratrol supplementation on suppression of atherogenic lesion formation and cholesterol synthesis in apo E-deficient mice. Biochem Biophys Res Commun 374:55–59CrossRefPubMed
go back to reference Garcea G, Manson M, Neal C, Pattenden C, Sutton C, Dennison A, Berry D (2007) Glycogen synthase kinase-3 beta; A new target in pancreatic cancer? Curr Cancer Drug Tar 7:209–215CrossRef Garcea G, Manson M, Neal C, Pattenden C, Sutton C, Dennison A, Berry D (2007) Glycogen synthase kinase-3 beta; A new target in pancreatic cancer? Curr Cancer Drug Tar 7:209–215CrossRef
go back to reference Gunningham SP, Currie MJ, Han C, Robinson BA, Scott PA, Harris AL, Fox SB (2001a) VEGF-B expression in human primary breast cancers is associated with lymph node metastasis but not angiogenesis. J Pathol 193:325–332CrossRefPubMed Gunningham SP, Currie MJ, Han C, Robinson BA, Scott PA, Harris AL, Fox SB (2001a) VEGF-B expression in human primary breast cancers is associated with lymph node metastasis but not angiogenesis. J Pathol 193:325–332CrossRefPubMed
go back to reference Gunningham SP, Currie MJ, Han C, Turner K, Scott PA, Robinson BA, Harris AL, Fox SB (2001b) Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas regulation by the von Hippel-Lindau gene and hypoxia. Cancer Res 61:3206–3211PubMed Gunningham SP, Currie MJ, Han C, Turner K, Scott PA, Robinson BA, Harris AL, Fox SB (2001b) Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas regulation by the von Hippel-Lindau gene and hypoxia. Cancer Res 61:3206–3211PubMed
go back to reference Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I et al (2010) Vanwildemeersch, vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464:917–921CrossRefPubMed Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I et al (2010) Vanwildemeersch, vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464:917–921CrossRefPubMed
go back to reference Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C (2008) Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8:82CrossRefPubMedPubMedCentral Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C (2008) Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8:82CrossRefPubMedPubMedCentral
go back to reference Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG et al (2003) Sinclair, Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196CrossRefPubMed Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG et al (2003) Sinclair, Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196CrossRefPubMed
go back to reference Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249CrossRefPubMed Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249CrossRefPubMed
go back to reference Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S (2011) Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol-and melatonin-induced cardioprotection. J Pineal Res 50:374–380CrossRefPubMed Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S (2011) Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol-and melatonin-induced cardioprotection. J Pineal Res 50:374–380CrossRefPubMed
go back to reference Leis H, Segrelles C, Ruiz S, Santos M, Paramio JM (2002) Expression, localization, and activity of glycogen synthase kinase 3β during mouse skin tumorigenesis. Mol Carcinogen 35:180–185CrossRef Leis H, Segrelles C, Ruiz S, Santos M, Paramio JM (2002) Expression, localization, and activity of glycogen synthase kinase 3β during mouse skin tumorigenesis. Mol Carcinogen 35:180–185CrossRef
go back to reference Li X, Lee C, Tang Z, Zhang F, Arjunan P, Li Y, Hou X, Kumar A, Dong L (2009) VEGF-B: a survival, or an angiogenic factor? Cell Adhes Migr 3:322–327CrossRef Li X, Lee C, Tang Z, Zhang F, Arjunan P, Li Y, Hou X, Kumar A, Dong L (2009) VEGF-B: a survival, or an angiogenic factor? Cell Adhes Migr 3:322–327CrossRef
go back to reference Liao PC, Ng LT, Lin LT, Richardson CD, Wang GH, Lin CC (2010) Resveratrol arrests cell cycle and induces apoptosis in human hepatocellular carcinoma Huh-7 cells. J Med Food 13:1415–1423CrossRefPubMed Liao PC, Ng LT, Lin LT, Richardson CD, Wang GH, Lin CC (2010) Resveratrol arrests cell cycle and induces apoptosis in human hepatocellular carcinoma Huh-7 cells. J Med Food 13:1415–1423CrossRefPubMed
go back to reference Mai W, Kawakami K, Shakoori A, Kyo S, Miyashita K, Yokoi K, Jin M, Shimasaki T, Motoo Y, Minamoto T (2009) Deregulated GSK3β sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase. Clin Cancer Res 15:6810–6819CrossRefPubMed Mai W, Kawakami K, Shakoori A, Kyo S, Miyashita K, Yokoi K, Jin M, Shimasaki T, Motoo Y, Minamoto T (2009) Deregulated GSK3β sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase. Clin Cancer Res 15:6810–6819CrossRefPubMed
go back to reference Mamaghani S, Patel S, Hedley DW (2009) Glycogen synthase kinase-3 inhibition disrupts nuclear factor-kappaB activity in pancreatic cancer, but fails to sensitize to gemcitabine chemotherapy. BMC Cancer 9:132CrossRefPubMedPubMedCentral Mamaghani S, Patel S, Hedley DW (2009) Glycogen synthase kinase-3 inhibition disrupts nuclear factor-kappaB activity in pancreatic cancer, but fails to sensitize to gemcitabine chemotherapy. BMC Cancer 9:132CrossRefPubMedPubMedCentral
go back to reference Miki H, Uehara N, Kimura A, Sasaki T, Yuri T, Yoshizawa K, Tsubura A (2012) Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells. Int J Oncol 40:1020–1028PubMedPubMedCentral Miki H, Uehara N, Kimura A, Sasaki T, Yuri T, Yoshizawa K, Tsubura A (2012) Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells. Int J Oncol 40:1020–1028PubMedPubMedCentral
go back to reference Mo W, Xu X, Xu L, Wang F, Ke A, Wang X, Guo C (2011) Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cell. Pancreatology 11:601–609CrossRefPubMed Mo W, Xu X, Xu L, Wang F, Ke A, Wang X, Guo C (2011) Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cell. Pancreatology 11:601–609CrossRefPubMed
go back to reference Mylona E, Alexandrou P, Giannopoulou I, Liapis G, Sofia M, Keramopoulos A, Nakopoulou L (2007) The prognostic value of vascular endothelial growth factors (VEGFs)-A and-B and their receptor, VEGFR-1, in invasive breast carcinoma. Gynecol Oncol 104:557–563CrossRefPubMed Mylona E, Alexandrou P, Giannopoulou I, Liapis G, Sofia M, Keramopoulos A, Nakopoulou L (2007) The prognostic value of vascular endothelial growth factors (VEGFs)-A and-B and their receptor, VEGFR-1, in invasive breast carcinoma. Gynecol Oncol 104:557–563CrossRefPubMed
go back to reference Nakagawa H, Kiyozuka Y, Uemura Y, Senzaki H, Shikata N, Hioki K, Tsubura A (2001) Resveratrol inhibits human breast cancer cell growth and may mitigate the effect of linoleic acid, a potent breast cancer cell stimulator. J Cancer Res Clin Oncol 127:258–264CrossRefPubMed Nakagawa H, Kiyozuka Y, Uemura Y, Senzaki H, Shikata N, Hioki K, Tsubura A (2001) Resveratrol inhibits human breast cancer cell growth and may mitigate the effect of linoleic acid, a potent breast cancer cell stimulator. J Cancer Res Clin Oncol 127:258–264CrossRefPubMed
go back to reference Olofsson B, Pajusola K, Kaipainen A, Von Euler G, Joukov V, Saksela O et al (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93:2576–2581CrossRefPubMedPubMedCentral Olofsson B, Pajusola K, Kaipainen A, Von Euler G, Joukov V, Saksela O et al (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93:2576–2581CrossRefPubMedPubMedCentral
go back to reference Ougolkov AV, Fernandez-Zapico ME, Savoy DN et al (2005) Glycogen synthase 3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res 65:2076–2081CrossRefPubMed Ougolkov AV, Fernandez-Zapico ME, Savoy DN et al (2005) Glycogen synthase 3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res 65:2076–2081CrossRefPubMed
go back to reference Shakoori A, Ougolkov A, Yu ZW, Zhang B, Modarressi MH, Billadeau DD, Mai M, Takahashi Y, Minamoto T (2005) Deregulated GSK3β activity in colorectal cancer: its association with tumor cell survival and proliferation. Biochem Biophys Res Commun 334:1365–1373CrossRefPubMed Shakoori A, Ougolkov A, Yu ZW, Zhang B, Modarressi MH, Billadeau DD, Mai M, Takahashi Y, Minamoto T (2005) Deregulated GSK3β activity in colorectal cancer: its association with tumor cell survival and proliferation. Biochem Biophys Res Commun 334:1365–1373CrossRefPubMed
go back to reference Shan Z, Yang G, Xiang W, Pei-Jun W, Bin Z (2014) Effects of resveratrol on oral squamous cell carcinoma (OSCC) cells in vitro. J Cancer Res Clin Oncol. doi:10.1007/s00432-013-1575-1 Shan Z, Yang G, Xiang W, Pei-Jun W, Bin Z (2014) Effects of resveratrol on oral squamous cell carcinoma (OSCC) cells in vitro. J Cancer Res Clin Oncol. doi:10.​1007/​s00432-013-1575-1
go back to reference Takaoka M (1940) Of the phenolic substances of white hellebore (Veratrum grandiflorum Loes. fil.). J Fac Sci Hokkaido Imp Univ 3:1–16 Takaoka M (1940) Of the phenolic substances of white hellebore (Veratrum grandiflorum Loes. fil.). J Fac Sci Hokkaido Imp Univ 3:1–16
go back to reference Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A (2006) Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 16:296–300CrossRefPubMed Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A (2006) Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 16:296–300CrossRefPubMed
go back to reference Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:686–689CrossRefPubMed Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:686–689CrossRefPubMed
go back to reference Yang L, Cai X, Liu J, Jia Z, Jiao J, Zhang J, Li C, Li J, Tang XD (2013) CpG-ODN attenuates pathological cardiac hypertrophy and heart failure by activation of PI3Kα-Akt signaling. PLoS ONE 8:e62373CrossRefPubMedPubMedCentral Yang L, Cai X, Liu J, Jia Z, Jiao J, Zhang J, Li C, Li J, Tang XD (2013) CpG-ODN attenuates pathological cardiac hypertrophy and heart failure by activation of PI3Kα-Akt signaling. PLoS ONE 8:e62373CrossRefPubMedPubMedCentral
go back to reference Zhou W, Wang L, Gou SM, Wang TI, Zhang M, Liu T, Wang CY (2012) ShRNA silencing glycogen synthase kinase-3 beta inhibits tumor growth and angiogenesis in pancreatic cancer. Cancer Lett 316:178–186CrossRefPubMed Zhou W, Wang L, Gou SM, Wang TI, Zhang M, Liu T, Wang CY (2012) ShRNA silencing glycogen synthase kinase-3 beta inhibits tumor growth and angiogenesis in pancreatic cancer. Cancer Lett 316:178–186CrossRefPubMed
Metadata
Title
Resveratrol plays dual roles in pancreatic cancer cells
Authors
Lei Yang
Liang Yang
Wencong Tian
Jing Li
Jie Liu
Mengmeng Zhu
Yan Zhang
Yinan Yang
Fei Liu
Qiong Zhang
Qianqian Liu
Yanna Shen
Zhi Qi
Publication date
01-05-2014
Publisher
Springer Berlin Heidelberg
Published in
Journal of Cancer Research and Clinical Oncology / Issue 5/2014
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-014-1624-4

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